2,3-substituted indole compounds as anti-inflammatory and analgesic agents

ABSTRACT

This invention provides a compound of the following formula:                    
     or the pharmaceutically acceptable salts thereof wherein Z is OH, C1-6 alkoxy, —NR2R3 or heterocycle; Q is selected from the following: (a) an optionally substituted phenyl, (b) an optionally substituted 6-membered monocyclic aromatic group containing one, two, three or four nitrogen atom(s), (c) an optionally substituted 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, (d) an optionally substituted C3-7 cycloalkyl and (e) an optionally substituted benzo-fuzed heterocycle; R1 is hydrogen, C1-4 alkyl or halo; R2 and R3 are independently hydrogen, OH, C1-4 alkoxy, C1-4 alkyl or C1-4 alkyl substituted with halo, OH, C1-4 alkoxy or CN; X is independently selected from H, halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino and CN; and n is 0, 1, 2, 3 and 4. 
     This invention also provides a pharmaceutical composition useful for the treatment of a medical condition in which prostaglandins are implicated as pathogens.

This application is a 371 of International Application No.PCT/IB98/02065, filed Dec. 18, 1998, which claims the benefit ofInternational Application No. PCT/IB98/00003, filed Jan. 5, 1998.

TECHNICAL FIELD

This invention relates to novel 2,3-substituted indoles aspharmaceutical agents. This invention specifically relates to compounds,compositions and methods for the treatment or alleviation of pain andinflammation and other inflammation-associated disorders, such asarthritis.

BACKGROUND ART

Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used in treatingpain and the signs and symptoms of arthritis because of their analgesicand anti-inflammatory activity. It is accepted that common NSAIDs workby blocking the activity of cyclooxygenase (COX), also known asprostaglandin G/H synthase (PGHS), the enzyme that converts arachidonicacid into prostanoids. Prostaglandins, especially prostaglandin E₂(PGE₂), which is the predominant eicosanoid detected in inflammationconditions are mediators of pain, fever and other symptoms associatedwith inflammation. Inhibition of the biosynthesis of prostaglandins hasbeen a therapeutic target of anti-inflammatory drug discovery. Thetherapeutic use of conventional NSAIDs is, however, limited due to drugassociated side effects, including life threatening ulceration and renaltoxicity. An alternative to NSAIDs is the use of corticosteriods,however, long term therapy can also result in severe side effects.

Recently, two forms of COX were identified, a constitutive isoform(COX-1) and an inducible isoform (COX-2) of which expression isupregulated at sites of inflammation (Vane, J. R.; Mitchell, J. A.;Appleton, I.; Tomlinson, A.; Bishop-Bailey, D.; Croxtoll, J.;Willoughby, D. A. Proc. Natl. Acad Sci. USA, 1994, 91, 2046). COX-1 isthought to play a physiological role and to be responsible forgastrointestinal and renal protection. On the other hand, COX-2 appearsto play a pathological role and to be the predominant isoform present ininflammation conditions. A pathological role for prostaglandins has beenimplicated in a number of human disease states including rheumatoid andosteoarthritis, pyrexia, asthma, bone resorption, cardiovasculardiseases, nephrotoxicity, atherosclerosis, hypotension, shock, pain,cancer, and Alzheimer disease. The NSAIDs currently on market inhibitboth isoforms of COX with little variation for selectivity, explainingtheir beneficial (inhibition of COX-2) and deleterious effects(inhibition of COX-1). It is believed that compounds that wouldselectively inhibit the biosynthesis of prostaglandins by interventionof the induction phase of the inducible enzyme cyclooxygenase-2 and/orby intervention of the activity of the enzyme cyclooxygenase-2 onarachidonic acid would provide alternate therapy to the use of NSAIDs orcorticosteriods in that such compounds would exert anti-inflammatoryeffects without the adverse side effects associated with COX-1inhibition.

A variety of indole compounds are known and are disclosed in severalpatent applications. The International Publication Numbers WO 96/32379discloses N-substituted indole compounds as cGMP-PDE Inhibitors. TheInternational Publication Numbers WO 96/37467, WO 96/37469, UK PatentPublication GB 2283745 A and U.S. Pat. No. 5,510,368 disclose2-methyl-N-substituted indole compounds as cyclooxygenase-2 Inhibitors.Also, a variety of indole compounds are disclosed as agents forcontrolling underwater fouling organisms in European Patent PublicationNumber 0 556 949 A2 by Konya, Kazumi et. al. Specifically, theInternational Publication Numbers WO 97/09308 discloses indole compoundsas neuropeptide receptor antagonists. Besides, in Sci. Pharm. 64, 577(1996), a process for preparing a 2-ester-substituted indoline isdisclosed.

BRIEF DISCLOSURE OF THE INVENTION

The present invention provides a compound of the following formula:

or the pharmaceutically acceptable salts thereof wherein

Z is OH, C₁₋₆ alkoxy, —NR²R³ or a group of the formula (II) or (III):

wherein r is 1, 2, 3 or 4, Y is a direct bond, O, S or NR⁴, and W is OHor —NR²R³;

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl optionally substituted with one or two substituentsindependently selected from OH, C₁₋₄ alkyl, halo and halo-substitutedC₁₋₄ alkyl; and

(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1);

R¹ is hydrogen, C₁₋₄ alkyl or halo;

R² and R³ are independently H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl or C₁₋₄ alkylsubstituted with halo, OH, C₁₋₄ alkoxy, NH₂ or CN;

R⁴ is hydrogen or C₁₋₄ alkyl;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄alkylsulfonylamino and C₃₋₇ cycloalkyl; and

n is 0, 1, 2, 3 or 4.

The indole compounds of the present invention exhibit inhibition of COXactivity. Preferably compounds of this invention exhibit inhibitoryactivity against COX-2, with more preferable compounds having COX-2selectivity.

Accordingly, the present invention also provides a pharmaceuticalcomposition, useful for the treatment of a medical condition in whichprostaglandins are implicated as pathogens, which comprises a compoundof the formula (I) and the pharmaceutically acceptable salts thereof.

Further, the present invention provides a method for the treatment of amedical condition in which prostaglandins are implicated as pathogens,in a mammalian subject, which comprises administering to said subject atherapeutically effective amount of said pharmaceutical composition.

The medical conditions in which prostaglandins are implicated aspathogens, include the relief of pain, fever and inflammation of avariety of conditions including rheumatic fever, symptoms associatedwith influenza or other viral infections, common cold, low back and neckpain, dysmenorrhea, headache, toothache, sprains and strains, myositis,neuralgia, synovitis, arthritis including rheumatoid arthritis,degenerative joint disease (osteoarthritis), gout, ankylosingspondylitis, systemic lumpus erythematosus and juvenile arthritis,bursitis, burns, injuries following surgical and dental procedures.

The compounds and pharmaceutical composition of this invention mayinhibit cellular neoplastic transformations and metastatic tumor growthand thus may be used in the treatment and/or prevention of cancers inthe colon, breast, skin, esophagus, stomach, urinary bladder, lung andliver. The compounds and pharmaceutical composition of this inventionwere used in the treatment and/or prevention of cyclooxygenase-mediatedproliferation disorders such as which occur in diabetic retinopathy andtumor angiogenesis.

The compounds and pharmaceutical composition of this invention mayinhibit prostaniod-induced smooth muscle contraction by preventing thesynthesis of contractile prostanoids, and thus may be of use in thetreatment of dysmenorrhea, premature labor, asthma and eosinophilrelated disorders and in the treatment of neurodegenerative diseasessuch as Alzheimer's and Parkinson's disease, and for the treatment ofbone loss (treatment of osteoarthritis), stroke, seizures, migraine,multiple sclevosis, AIDS and encephaloathy.

By virtue of the COX-2 activity and/or specificity for COX-2 over COX-1,such compounds will prove useful as an alternative to conventionalNSAIDs particularly where such NSAIDs may be contra-indicated such as inpatients with ulcers (such as peptic ulcers and gastric ulcers),gastritis, regional enterotis, ulcerative colitis, diverticulitis orwith a recurrent history of GI lesions, GI bleeding, coagulationdisorders including anemia such as hypoprothrombinemia, haemophilia andother bleeding problems; kidney disease; prior to surgery of taking ofanticoagulants.

Also, the present invention provides a compound of formula 7-VI:

wherein B is a suitable protecting group;

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl optionally substituted with one or two substituentsindependently selected from OH, C₁₋₄ alkyl, halo and halo-substitutedC₁₋₄ alkyl; and

(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1);

R² and R³ are independently H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl or C₁₋₄ alkylsubstituted with halo, OH, C₁₋₄ alkoxy, NH₂ or CN;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄alkylsulfonylamino and C₃₋₇ cycloalkyl; R⁵ is C₁₋₆ alkyl; and

n is 0, 1, 2, 3 or 4.

Also, the present invention provides a compound of formula 7-V:

wherein B is a suitable protecting group;

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl optionally substituted with one or two substituentsindependently selected from OH, C₁₋₄ alkyl, halo and halo-substitutedC₁₋₄ alkyl; and

(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1);

R² and R³ are independently H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl or C₁₋₄ alkylsubstituted with halo, OH, C₁₋₄ alkoxy, NH₂ or CN;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄alkylsulfonylamino and C₃₋₇ cycloalkyl; R⁵ is C₁₋₆ alkyl; and

n is 0, 1, 2, 3 or 4.

DETAILED DISCLOSURE OF THE INVENTION

As used herein, “halo” is fluoro, chloro, bromo or iodo.

As used herein, the term “C₁₋₄ alkyl” means straight or branched chainsaturated radicals of 1 to 4 carbon atoms, including, but not limited tomethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, and the like.

As used herein, an example of “propyl” is n-propyl and isopropyl.

As used herein, an example of “butyl” is n-butyl, isobutyl, sec-butyland tert-butyl.

As used herein, an example of “alkoxy” is methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

As used herein, an example of “alkylthio” is methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio,tert-butylthio, and the like.

As used herein, an example of “di-(C₁₋₄ alkyl)amino” is dimethylamino,diethylamino, dipropylamino, N-methyl-N-ethylamino,N-methyl-N-propylamino, N-methyl-N-butylamino, N-ethyl-N-propylamino,and the like.

As used herein, an example of “C₁₋₄ alkylamino” is methylamino,ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino,sec-butylamino, tert-butylamino, and the like.

As used herein, an example of “HO—(C₁₋₄)alkyl” is hydroxymethyl,hydroxyethyl (e.g., 1-hydroxyethyl and 2-hydroxyethyl), hydroxypropyl(e.g., 1-hydroxypropyl, 2-hydroxypropyl and 3-hydroxypropyl).

As used herein, an example of “C₁₋₄ alkoxy-C₁₋₄ alkyl” is methoxymethyl,methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl,ethoxypropyl, and the like.

As used herein, the term “halo-substituted alkyl” refers to an alkylradical as described above substituted with one or more halogensincluded, but not limited to, chloromethyl, dichloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, andthe like.

As used herein, an example of “halo-substituted alkoxy” ischloromethoxy, dichloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, 2,2,2-trichloroethoxy, and the like.

As used herein, the term “C₃₋₇ cycloalkyl” means carbocyclic radicals,of 3 to 7 carbon atoms, including, but not limited to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

As used herein, an example of “aryl” is phenyl and naphthyl.

As used herein, a 5-membered monocyclic aromatic group usually has oneheteroatom selected from O, S and N in the ring. In addition to saidheteroatom, the monocyclic aromatic group may optionally have up tothree N atoms in the ring. For example, the 5-membered monocyclicaromatic group includes thienyl, furyl, thiazolyl (e.g., 1,3-thiazolyl,1,2-thiazolyl), imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl,1,2-oxazolyl, isoxazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g.,1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g.,1,2.3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl,1,2,3-thiadiazolyl) and the like.

As used herein, an example of a 6-membered monocyclic aromatic groupincludes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (e.g.,1,3,5-triazinyl), tetrazinyl and the like.

As used herein, an example of a benzo-fuzed heterocycle includesquinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, benzoimidazolyl,benzothiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl,isoindolyl, 1H-indazolyl, quinazolinyl, phthalazinyl and the like.

As used herein, an example of (ethyl)(ethoxy)pyridyl includes3-ethoxy-4-ethyl-2-pyridyl, 4-ethoxy-3-ethyl-2-pyridyl and the like.

As used herein, an example of (chloro)(ethyl)pyridyl includes3-chloro-4-ethyl-2-pyridyl, 4-chloro-3-ethyl-2-pyridyl and the like.

As used herein, an example of (fluoro)(ethyl)phenyl includes3-fluoro-4-ethyl-2-pyridyl, 4-fluoro-3-ethyl-2-pyridyl and the like.

Preferred compounds of this invention are those of the formula (I)wherein

Z is OH, C₁₋₆ alkoxy, dimethylamino, methylamino, amino,N-methoxy-N-methylamino, 2-cyanoethylamino, 2-hydroxyethylamino,pyrrolidinyl, piperidino, piperazinyl, N-methyl-piperazinyl, morpholino,methoxyamino, piperazynyl, aminopyrrolidinyl or aminoethylamino.

Further preferred compounds of this invention are those of the formula(I) wherein

Z is OH or C₁₋₆ alkoxy; and

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl, and the said cycloalkyl being optionally substitutedwith one substituent selected from OH, methyl, ethyl, propyl, F, Cl andCF₃; and

(e) a benzo-fuzed heterocycle selected from quinolyl, isoquinolyl,cinnolinyl, quinoxalinyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl,benzofuranyl, benzothiophenyl and indolyl, and the benzo-fuzedheterocycle being optionally substituted with one, two, or threesubstituents independently selected from the group (a-1).

Further preferred compounds of this invention are those of the formula(I) wherein

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) cyclopropyl, cyclobutyl and cyclohexyl; and

(e) quinolyl or isoquinolyl, and said quinolyl or isoquinolyl beingoptionally substituted with one substituent selected from the grouphalo, C₁₋₄ alkyl, NH₂, OH, C₁₋₄ alkoxy and C₁₋₄ halo-substituted alkyl.

Further preferred compounds of this invention are those of the formula(I) wherein

Z is OH, C₁₋₆ alkoxy;

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4); and

(e) isoquinolyl;

R¹ is hydrogen or C₁₋₄ alkyl;

R² and R³ are independently H or methyl;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthioNO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOR⁴, C₁₋₄ alkylsulfonylamino and C₃₋₇cycloalkyl; and

n is 0, 1, 2, or 3.

Further preferred compounds of this invention are those of the formula(I) wherein

Z is OH, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxyor tert-butoxy;

Q is selected from the following:

(a) phenyl optionally substituted with one or two substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, HO—(C₁₋₄)alkyl, C₁₋₄alkoxy-C₁₋₄ alkyl, —COOH, C₁₋₄ alkylsulfonylamino, nitro, C₁₋₄alkylsulfonyl and cyano,

(a-2) phenyl or benzyloxy, and the phenyl or phenyl moiety of benzyloxybeing optionally substituted with one substituent selected from C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, halo, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy and NH₂,

(a-3) 5-membered monocyclic aromatic group selected from imidazolyl,thiazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, triazolyl, oxazolyl,isoxazolyl, thiadiazolyl and pyrazolyl, and the 5-membered monocyclicaromatic group optionally being substitued with one substituent selectedfrom C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, halo, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy and NH₂,

(a-4) 6-membered monocyclic aromatic group selected from pyridyl,pyrazinyl, pyrimidinyl and pyridazinyl, and the 6-membered monocyclicaromatic group optionally being substitued with one substituent selectedfrom C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, halo, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy and NH₂,

(b) a 6-membered monocyclic aromatic group selected from pyridyl,pyrazinyl, pyrimidinyl and pyridazinyl, and said monocyclic armomaticgroup being optionally substituted with one or two substituentsindependently selected from the above group (a-1), (a-2), (a-3) and(a-4),

(c) a 5-membered monocyclic aromatic group selected from imidazolyl,thiazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, triazolyl, oxazolyl,isoxazolyl, thiadiazolyl and pyrazolyl, and said monocyclic aromaticgroup being optionally substituted with one or two substituentsindependently selected from the above group (a-1), (a-2), (a-3) and(a-4);

R¹ is hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butylor tert-butyl;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl and aminosulfonyl; and

n is 0, 1, 2, or 3.

Further preferred compounds of this invention are those of the formula(I) wherein

Z is OH, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxyoror tert-butoxy;

Q is selected from the following:

(a) phenyl optionally substituted with one or two substituentsindependently selected from

(a-1) fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, CH₂F,CHF₂, CF₃, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, CH₂F—O—,CHF₂—O—, CF₃—O—, methylthio, ethylthio, hydroxymethyl, methoxymethyl,methoxyethyl, ethoxymethyl, hydroxy, nitro, methylsulfonyl, cyano,(HO)(H₃C)₂C—, acetyl and methylsulfonylamino,

(a-2) phenyl or benzyloxy, and the phenyl or phenyl moiety of benzyloxybeing optionally substituted with one substituent selected from methyl,ethyl, propyl, CF₃, F, Cl, OH, methoxy, ethoxy and NH₂,

(a-3) 5-membered monocyclic aromatic group selected from furyl, thienyland pyrrolyl, and the 5-membered monocyclic aromatic group optionallybeing substitued with one substituent selected from methyl, ethyl,propyl, CF₃, F, Cl, OH, methoxy, ethoxy and NH₂,

(a-4) pyridyl optionally substitued with one substituent selected frommethyl, ethyl, propyl, CF₃, F, Cl, OH, methoxy, ethoxy and NH₂,

(b) pyridyl optionally substituted with one, two or three substituentsindependently selected from the above group (a-1), (a-1), (a-2), (a-3)and (a-4),

(c) imidazolyl, thiazolyl, furyl, thienyl, isoxazolyl,1,2,3-thiadiazolyl or pyrrolyl, and said imidazolyl, thiazolyl, furyl,thienyl, isoxazolyl, 1,2,3-thiadiazolyl or pyrrolyl being optionallysubstituted with one or two substituents independently selected from theabove group (a-1), (a-2), (a-3) and (a-4);

R¹ is hydrogen, methyl, ethyl, n-propyl, iso-propyl;

X is independently selected from fluoro, chloro, bromo, methyl, ethyl,propyl, butyl, CH₂F, CHF₂, CF₃, methoxy, CF₃O or ethoxy; and

n is 0, 1 or 2.

Further preferred compounds of this invention are those of the formula(I) wherein

Z is OH, ethoxy or methoxy; Q is phenyl, chlorophenyl, fluorophenyl,bromophenyl, methylphenyl, methoxyphenyl, (furyl)phenyl,trifluoromethylphenyl, trifluoromethoxyphenyl, pyridyl, methylpyridyl,ethylpyridyl, propylpyridyl, dimethlylpyridyl, chloropyridyl,fluoropyridyl, trifluoromethylpyridyl, methoxypyridyl,(ethyl)(ethoxy)pyridyl, (chloro)(ethyl)pyridyl, thiazolyl,methylthiazolyl, furyl, methoxymethylfuryl, isoquinolyl, cyclohexyl,methoxyphenyl, (fluoro)(ethyl)pyridyl, dimethylpyridyl or(ethoxy)(ethyl)pyridyl;

R¹ is hydrogen; X is fluoro, chloro, methyl, ethyl, isopropyl,tert-butyl, CF₃ or methoxy; and n is 1 or 2.

Further preferred compounds of this invention are those of the formula(I) wherein

Z is OH, ethoxy or methoxy; Q is phenyl, chlorophenyl, pyridyl,methylpyridyl, ethylpyridyl, propylpyridyl or chloropyridyl; R¹ ishydrogen; X is fluoro, chloro, methyl or CF₃; and n is 1 or 2.

Preferred individual compounds of this invention are:

ethyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid, sodium salt;

[6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid;

(2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid;

[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

(2-benzoyl-7-chloro-1H-indol-3-y)acetic acid;

(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

less polar antipode, 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

more polar antipode, 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

(2-benzoyl-6-chloro-1H-indol-3-yl)-N,N-dimethylacetamide;

(2-benzoyl-6-chloro-1H-indol-3-yl)-N-methylacetamide;

(2-benzoyl-6-chloro-1H-indol-3-yl)acetamide;

(2-benzoyl-6-chloro-1H-indol-3-yl)-N-methoxy-N-methylacetamide;

2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-piperidino-1-ethanone;

2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-(4-methyl-1-piperazinyl)-1-ethanone;

(2-benzoyl-6-chloro-1H-indol-3-yl)-N-(2-cyanoethyl)acetamide;

(2-benzoyl-6-chloro-1H-indol-3-yl)-N-(2-hydroxyethyl)acetamide;

2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-morpholino-1-ethanone;

[2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-ethyl pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetate;

[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid;

methyl[2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetate;

[2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]aceticacid;

methyl[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate;

[2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]aceticacid;

methyl[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]aceticacid;

methyl[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-methyl-2-(4-methyl pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

methyl[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

methyl(2-benzoyl-1H-indol-3-yl)acetate;

(2-benzoyl-1H-indol-3-yl)acetic acid;

methyl[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid;

methyl[6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl[2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetic acid;

methyl[2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetic acid;

methyl[2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetic acid;

methyl[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-benzoxybenzyloyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-cyanobenzoyl)-1H-indol-3-yl]acetate;

methyl[6-chloro-2-[4-bromobenzoyl]-1H-indol-3-yl]acetate;

methyl[6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(3-bromobenzoyl)-1H-indol-3-yl]acetate;

methyl[6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl dl-2-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]propionate;

dl-2-[2-(4-chlorobenzoyl)-6-chloro-1H-indol-3-yl]propionic acid;

methyl[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(isoquinolne-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2-thienyl)carbonylindol-3-yl]acetic acid;

methyl[6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetate;

methyl[5-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetic acid;

methyl(6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-[3-(ethoxypropyl)isoxazole-5-carbonyl]-1H-indol-3-yl]acetate;

[5-chloro-2-[3-(carboxy)isoxazole-5-carbonyl]-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetate;

[6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetate;

[6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl)acetic acid;

methyl[5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N,N-dimethylacetamide;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-methylacetamide;

[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-hydroxyethyl)acetamide;

[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-methoxyacetamide;

2-[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-piperazinyl-1-ethanone;

[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-aminoethyl)acetamide;

2-[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-(3-amino-1-pyrrolidinyl)-1-ethanone;

[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

methyl[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[6-chloro-2-(2-nitrobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2,4-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-difuluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2,5-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate;

methyl[6-fluoro-2-(4-methylpyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[6-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic acid,and a salt thereof.

Preferred individual compounds of this invention are:

ethyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid, sodium salt;

[6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid;

(2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid;

[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chloro benzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

(2-benzoyl-7-chloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

less polar antipode, 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

more polar antipode, 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3yl]acetate;

[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

[2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2-methylcarbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[6-chloro-2-(3-chloro-4-ethyl pyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]aceticacid;

[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]aceticacid;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]aceticacid;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

(2-benzoyl-1H-indol-3-yl)acetic acid;

[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid;

[6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-cyanobenzoyl)-1H-indol-3-yl]acetate;

methyl[6-chloro-2-[4-bromobenzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(3-bromobenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

dl-2-[2-(4-chlorobenzoyl)-6-chloro-1H-indol-3-yl]propionic acid;

[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]aceticacid;

[6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]aceticacid;

[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2-thienyl)carbonylindol-3-yl]acetic acid;

[6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]aceticacid;

[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-[3-(carboxy)isoxazole-5-carbonyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetic acid;

[6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetic acid;

[5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[6-chloro-2-(4-ethyl-3-fluoro-pyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[6-chloro-2-(2-nitrobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2,4-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-difuluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2,5-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid, and a saltthereof.

Preferred individual compounds of this invention are:

ethyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

(2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid;

[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

less polar antipode, 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

more polar antipode, 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(6-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

[6-chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetate;

[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5,6-dichloro-2-(4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]aceticacid;

methyl[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

methyl[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

methyl[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

methyl[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid;

methyl[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(5methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate, anda salt thereof.

Preferred individual compounds of this invention are:

ethyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

(2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid;

[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

less polar antipode, 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

more polar antipode, 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

[6-chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]aceticacid;

[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]aceticacid;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

2-{6-chloro-2-[(4-ethyl-3-fluoro-2-pyridinyl)carbonyl]-1H-indol-3-yl}aceticacid;

methyl[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate, anda salt thereof.

Preferred individual compounds of this invention are:

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl)acetate;

[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-y ]aceticacid;

methyl[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]aceticacid;

methyl[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate;

[2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]aceticacid;

methyl[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

methyl[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aacetate;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid;

methyl[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-trifluoromethy-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate, anda salt thereof.

Preferred individual compounds of this invention are:

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[62-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]aceticacid;

[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]aceticacid;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl]-1H-indol-3-yl)aceticacid;

methyl[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate;

[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid, anda salt thereof.

Preferred individual compounds of this invention are:

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetaticacid;

methyl[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

methyl[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid(cj-020,099);

methyl[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate,and a salt thereof.

Most preferred individual compounds are:

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid, and asalt thereof.

Preferred pharmaceutical compositions of this invention comprise thosecompounds of the formula (I), wherein the compound is as defined above.

Most preferred individual compounds to be contained in thepharmaceutical compositions are:

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1-indol-3-yl]aceticacid;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;

[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;

[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-methyl-2-(4-methyl pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid, and asalt thereof.

Also, the present invention provides a process for prepraing a compoundof the formula:

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl optionally substituted with one or two substituentsindependently selected from OH, C₁₋₄ alkyl, halo and halo-substitutedC₁₋₄ alkyl; and

(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1);

R² and R³ are independently H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl or C₁₋₄ alkylsubstituted with halo, OH, C₁₋₄ alkoxy, NH₂ or CN;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄alkylsulfonylamino and C₃₋₇ cycloalkyl; and

n is 0, 1, 2, 3 or 4,

which process comprises the steps of:

i) reacting a compound of the formula:

wherein B is a suitable protecting group; R⁵ is C₁₋₆ alkyl; X and n areas defined above, with a compound of the formula:

wherein E is halo and Q are as defined above, with a first base and asuitable solvent;

ii) reacting the product of step i) with a second base.

iii) reacting the product of step ii) with an acid.

Prefered process of the above mentioned process is a process, whereinsaid first base is potassium carbonate, potassium bicarbonate, sodiumbicarbonate, sodium carbonate or cesium carbonate.

Prefered process of the above mentioned process is a process, whereinsaid first base is potassium carbonate.

Prefered process of the above mentioned process is a process, whereinsaid second base is aqueous sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, sodium pentoxide (followed bywater), sodium methoxide (followed by water) or potassium t-butoxide(followed by water).

Prefered process of the above mentioned process is a process, whereinsaid second base is sodium hydroxide.

Prefered process of the above mentioned process is a process, whereinsaid acid is aqueous hydrochloric acid, hydrobromic acid, sulfuric acidor ammonium chloride.

Prefered process of the above mentioned process is a process, whereinsaid acid is aqueous hydrochloric acid.

Prefered process of the above mentioned process is a process, whereinsaid solvent is N,N-dimethylacetamide, N,N-dimethylformamide, methylethyl ketone, acetone, or tetrahydrofuran.

Prefered process of the above mentioned process is a process, whereinsaid solvent is N,N-dimethylaetamide.

Also, the present invention provides a process for prepraing a compoundof the formula:

wherein

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl optionally substituted with one or two substituentsindependently selected from OH, C₁₋₄ alkyl, halo and halo-substitutedC₁₋₄ alkyl; and

(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1);

R² and R³ are independently H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl or C₁₋₄ alkylsubstituted with halo, OH, C₁₋₄ alkoxy, NH₂ or CN;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄alkylsulfonylamino and C₃₋₇ cycloalkyl; and

n is 0, 1, 2, 3 or 4,

which process comprises reacting a compound of the formula:

wherein R⁵ is C₁₋₆ alkyl; Q, X and n are as defined as before, with abase in a suitable solvent.

Prefered process of the above mentioned process is a process, whereinsaid base is sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodiumt-pentoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide.

Prefered process of the above mentioned process is a process, whereinsaid base is sodium hydroxide.

Prefered process of the above mentioned process is a process, whereinsaid solvent is an aqueous mixture of methanol, ethanol, isopropylalcohol or tetrahydrofuran.

Prefered process of the above mentioned process is a process, whereinsaid solvent is methanol containing water.

Also, the present invention provides a process for prepraing a compoundof the formula:

wherein

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl optionally substituted with one or two substituentsindependently selected from OH, C₁₋₄ alkyl, halo and halo-substitutedC₁₋₄ alkyl; and

(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1);

R² and R³ are independently H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl or C₁₋₄ alkylsubstituted with halo, OH, C₁₋₄ alkoxy, NH₂ or CN;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄alkylsulfonylamino and C₃₋₇ cycloalkyl; R⁵ is C₁₋₆ alkyl; and

n is 0, 1, 2, 3 or 4,

which process comprises reacting a compound of the formula:

wherein B, Q, X, n and R⁵ are as defined above with a base in a suitablesolvent.

Prefered process of the above mentioned process is a process, whereinsaid base is 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-ene, 1,1,3,3-tetramethylguanidine, sodiumt-pentoxide, sodium methoxide, or potassium t-butoxide.

Prefered process of the above mentioned process is a process, whereinsaid base is 1,8-diazabicyclo[5.4.0]undec-7-ene or potassium t-butoxide.

Prefered process of the above mentioned process is a process, whereinsaid solvent is N,N-dimethylacetamide, N,N-dimethylformamide, methylethyl ketone, acetone, or tetrahydrofuran.

Prefered process of the above mentioned process is a process, whereinsaid solvent is N,N-dimethylacetamide.

Also, the present invention provides a process for prepraing a compoundof the formula:

wherein B is a suitable protecting group;

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl optionally substituted with one or two substituentsindependently selected from OH, C₁₋₄ alkyl, halo and halo-substitutedC₁₋₄ alkyl; and

(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1);

R² and R³ are independently H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl or C₁₋₄ alkylsubstituted with halo, OH, C₁₋₄ alkoxy, NH₂ or CN;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²NR³,acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇cycloalkyl; R⁵ is C₁₋₆ alkyl; and

n is 0, 1, 2, 3 or 4,

which process comprises reacting a compound of the formula:

wherein B, Q, X, n and R⁵ are as defined above, with a base in thepresence of a solvent.

Prefered process of the above mentioned process is a process, whereinsaid base is potassium carbonate, potassium bicarbonate, sodiumbicarbonate, sodium carbonate, or cesium carbonate.

Prefered process of the above mentioned process is a process, whereinsaid base is potassium carbonate.

Prefered process of the above mentioned process is a process, whereinsaid solvent is N,N-dimethylacetamide, N,N-dimethylformamide, methylethyl ketone, acetone, or tetrahydrofuran.

Prefered process of the above mentioned process is a process, whereinsaid solvent is N,N-dimethylacetamide.

Also, the present invention provides a process for prepraing a compoundof the formula:

wherein B is a suitable protecting group;

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl optionally substituted with one or two substituentsindependently selected from OH, C₁₋₄ alkyl, halo and halo-substitutedC₁₋₄ alkyl; and

(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1);

R² and R³ are independently H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl or C₁₋₄ alkylsubstituted with halo, OH, C₁₋₄ alkoxy, NH₂ or CN;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄alkylsulfonylamino and C₃₋₇ cycloalkyl; R⁵ is C₁₋₆ alkyl; and

n is 0, 1, 2, 3 or 4,

which comprises reacting a compound of the formula:

wherein B, X, n and R⁵ are as defined above, with a compound of theformula:

wherein E is halo and Q arc as defined above, with a base in thepresence of a solvent.

Prefered process of the above mentioned process is a process, whereinsaid base is potassium carbonate, potassium bicarbonate, sodiumbicarbonate, sodium carbonate, or cesium carbonate.

Prefered process of the above mentioned process is a process, whereinsaid base is potassium carbonate.

Prefered process of the above mentioned process is a process, whereinsaid solvent is N,N-dimethylacetamide, N,N-dimethylformamide, methylethyl ketone, acetone or tetrahydrofuran.

Prefered process of the above mentioned process is a process, whereinsaid solvent is N,N-dimethylacetamide.

Also, the present invention provides a process for prepraing a compoundof the formula:

wherein

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl optionally substituted with one or two substituentsindependently selected from OH, C₁₋₄ alkyl, halo and halo-substitutedC₁₋₄ alkyl; and

(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1);

R¹ is hydrogen, C₁₋₄ alkyl or halo;

R² and R³ are independently H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl or C₁₋₄ alkylsubstituted with halo, OH, C₁₋₄ alkoxy, NH₂ or CN;

R⁵ is C₁₋₆ alkyl;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄alkylsulfonylamino and C₃₋₇ cycloalkyl; and

n is 0, 1, 2, 3 or 4,

which process comprises treating a compound of the formula (X):

wherein R¹, R⁵, X, Q and n are as defined herein before, and B is asuitable protecting group, in the presence of a suitable base to obtaina compound of the formula (XII).

Also, the present invention provides a process for prepraing a compoundof the formula:

wherein

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl optionally substituted with one or two substituentsindependently selected from OH, C₁₋₄ alkyl, halo and halo-substitutedC₁₋₄ alkyl; and

(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1);

R¹ is hydrogen, C₁₋₄ alkyl or halo;

R² and R³ are independently H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl or C₁₋₄ alkylsubstituted with halo, OH, C₁₋₄ alkoxy, NH₂ or CN;

R⁵ is C₁₋₆ alkyl;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄alkylsulfonylamino and C₃₋₇ cycloalkyl; and

n is 0, 1, 2, 3 or 4,

which process comprises reacting a compound of the formula (IX):

wherein R¹, R⁵, X, and n are as defined above, and B is a suitableprotecting group, with a compound of the formula (XI):

in the presence of a suitable base at a temperature of −40° C. to 200°C. to obtain a compound of the formula (XII).

Prefered process of the above mentioned process is a process, whereinthe reaction is carried out at a temperature of 0° C. to 100° C.

Prefered process of the above mentioned process is a process, whereinthe suitable base is potassium carbonate, cesium carbonate, sodiumcarbonate, sodium tert-butoxide, potassium tert-butoxide, sodiumhydride, potassium hydride or potassium fluoride.

Prefered process of the above mentioned process is a process, whereinthe reaction is firstly carried out in the presence of a base for 2minutes to a day; and then, another base is added to the reactionmixture.

Prefered process of the above mentioned process is a process, whereinthe reaction is firstly carried out for 30 minutes to 8 hours.

Prefered process of the above mentioned process is a process, whereinthe suitable protecting group is methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl, benzyloxycarbonyl, phenylsulfonyl,p-toluenesulfonyl, methanesulfonyl or trifluoromethanesulfonyl.

Prefered process of the above mentioned process is a process, whereinthe suitable protecting group is phenylsulfonyl, p-toluenesulfonyl,methanesulfonyl or trifluoromethanesulfonyl.

Prefered process of the above mentioned process is a process, whereinthe first base is selected from sodium tert-butoxide, potassiumtert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate,sodium hydride, potassium hydride, sodium carbonate, potassiumcarbonate, cesium carbonate, potassium fluoride,1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, pyridine, pyrrolidine, triethylamine,diisopropylamine, diisopropylethylamine and diethylisopropylamine; andthe second base is selected from sodium tert-butoxide, potassiumtert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate,sodium hydride, potassium hydride, sodium carbonate, potassiumcarbonate, cesium carbonate, potassium fluoride,1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, pyridine, pyrrolidine, triethylamine,diisopropylamine, diisopropylethylamine and diethylisopropylamine.

Prefered process of the above mentioned process is a process, whereinthe first base is selected from potassium carbonate, cesium carbonate,sodium hydride and potassium fluoride; and the second base is selectedfrom 1,8-diazabicyclo[5.4.0]undec-7-ene, cesium carbonate, pyrrolidine,diisopropylamine, triethylamine, diethylisopropylamine anddiisopropylethylamine.

Prefered process of the above mentioned process is a process, whereinthe first base is potassium carbonate, cesium carbonate or potassiumfluoride; and the second base is 1,8-diazabicyclo[5.4.0]undec-7-ene,potassium tert-butoxide or cesium carbonate.

Prefered process of the above mentioned process is a process, whereinthe combination of the first base and the second base (first base/secondbase) is selected from potassiumcarbonate/1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate/cesiumcarbonate, cesium carbonate/potassium tert-butoxide, cesiumcarbonate/1,8-diazabicyclo[5.4.0]undec-7-ene and potassiumfluoride/1,8-diazabicyclo[5.4.0]undec-7-ene and potassiumfluoride/cesium carbonate.

Prefered process of the above mentioned process is a process, whereinthe combination of the first base and the second base (first base/secondbasse) is selected from potassiumcarbonate/1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate/cesiumcarbonate and cesium carbonate/potassium tert-butoxide.

Also, the present invention provides a process for prepraing a compoundof the formula:

wherein

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NO₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl optionally substituted with one or two substituentsindependently selected from OH, C₁₋₄ alkyl, halo and halo-substitutedC₁₋₄ alkyl; and

(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1);

R¹ is hydrogen, C₁₋₄ alkyl or halo;

R² and R³ are independently H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl or C₁₋₄ alkylsubstituted with halo, OH, C₁₋₄ alkoxy, NH₂ or CN;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄alkylsulfonylamino and C₃₋₇ cycloalkyl; and

n is 0, 1, 2, 3 or 4,

which process comprises treating a compound of the formula (X):

wherein R¹, R⁵, X, Q and n are as defined here before, with a suitablebase under hydrolyzing conditions to obtain the compound of formula(VIII).

This invention also provides a process for preparing a compound of theformula (VIII):

wherein

Q is selected from the following:

(a) phenyl optionally substituted with one, two or three substituentsindependently selected from

(a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl,

(a-2) aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety beingoptionally substituted with one, two or three substituents independentlyselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN,

(a-3) 5-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(a-4) 6-membered monocyclic aromatic group optionally substitued withone, two or three substituents independently selected from halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino and CN,

(b) a 6-membered monocyclic aromatic group containing one, two, three orfour nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4),

(c) a 5-membered monocyclic aromatic group containing one heteroatomselected from O, S and N and optionally containing one, two or threenitrogen atom(s) in addition to said heteroatom, and said monocyclicaromatic group being optionally substituted with one, two or threesubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4);

(d) C₃₋₇ cycloalkyl optionally substituted with one or two substituentsindependently selected from OH, C₁₋₄ alkyl, halo and halo-substitutedC₁₋₄ alkyl; and

(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1);

R¹ is hydrogen, C₁₋₄ alkyl or halo;

R² and R³ are independently H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl or C₁₋₄ alkylsubstituted with halo, OH, C₁₋₄ alkoxy, NH₂ or CN;

X is independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄alkylsulfonylamino and C₃₋₇ cycloalkyl; and

n is 0, 1, 2, 3 or 4,

which process comprises hydrolyzing a compound of the formula (XII):

wherein R⁵ is C₁₋₆ alkyl, R¹, X, Q and n are as defined herein before.

General Synthesis

A compound of general formula (I) may be prepared by any syntheticprocedure applicable to structure-related compounds known to thoseskilled in the art. The following representative examples as describedhereinafter are illustrative and are not meant to limit the scope of theinvention in anyway. Unless otherwise stated, Q, X, Z, R¹, and n are asdefined above.

Scheme 1:

In one embodiment, for example, a compound of the formula (VI) may beprepared according to the reaction sequences depicted in Scheme 1.(Compound (VI) corresponds to a compound (I) wherein R¹ is H, and Z isOH.)

In brief, a compound of formula (III) is subjected to oxidativehomolytic malonylation (for leading references see J. M. Muchowski etal; Can. J. Chem., 70, 1838, 1992 and E. Baciocchi et al; J. Org. Chem.,58, 7610, 1993). In one example, a compound of the formula (III) isreacted with a suitable malonyl radical generated from a compound offormula C(R⁴)H(CO₂R⁵)₂, wherein R⁴ is hydrogen or halogen, preferablychloro, and R⁵ is C₁₋₆ alkyl, and a manganese(III) agent, preferablymanganese(III) triacetate. The manganese(III) agent is usually used instoichiometric amounts but, alternatively, may be made catalytic by useof a suitable reoxidizing agent such as sodium persulfate, usually inthe presence of a co-catalyst such as, a silver(I) salt such as silvernitrate. A preferred reaction solvent is acetic acid; however, aceticacid-acetic anhydride or other protic solvents such as propionic acidcan be used. The reaction is preferably conducted in the presence ofsodium acetate or potassium acetate, but, may be conducted in solventalone. Reaction temperatures are generally in the range of roomtemperature (e.g., 25° C.) to reflux temperature of solvent, preferably60 to 100° C., but if necessary, lower or higher temperature can beemployed. Reaction times are, in general, from one hour to a day,preferably from 4 to 16 hours, however shorter or longer reaction times,if necessary, can be employed. In the immediate instance, the α-acetoxycompounds of formula (IV) is usually obtained as the major product.Compounds of formula (IV) can readily be transformed to compounds offormula (V) by reduction with a suitable reducing agent, for example, atrialkylsilane, sodium α-(dimethylamino)naphtalenide, lithium in liquidammonia, sodium naphtalenide, preferably triethylsilane in a suitableprotic solvent, notably, trifluoroacetic acid. Alternatively, thereaction can be conducted in a reaction inert co-solvent such asdichloromethane or 1,2-dichloroethane. Reaction temperatures aregenerally in the range of room temperature to reflux temperature ofsolvent, preferably 15 to 100° C., but if necessary, lower or highertemperature can be employed. Reaction times are, in general, fromseveral minutes to a day, preferably from 20 minutes to 5 hours, howevershorter or longer reaction times, if necessary, can be employed.Alternatively, a compound of formula (V) may be obtained directly from acompound of formula (III) from a malonyl radical generated from (i) asuitable monohalomalonate, preferably, bromomalonate, mediated by aerialoxidation of a trialkylborane such as triethylborane (see B. Giese; InRadicals in organic synthesis: formation of carbon-carbon bonds.Pergamon Press, Oxford. pp. 86-89, 1986, and P. G. Allies and P. B.Brindley; J. Chem. Soc. (B), 1126, 1960) or, (ii) a malonic ester in thepresence of a cerium(IV) salt such as cerium(IV) ammonium nitrate (forexample, see E. Baciocchi et al; Tetrahedron Lett, 2763, 1986). Acompound of formula (V) may be readily transformed to a compound offormula (VI) by subjection to standard saponification/decarboxylationconditions.

Scheme 2:

Alternatively, as depicted in Scheme 2, a compound of the formula (VIII)(a compound (I) wherein Z is OH), wherein R¹ is C₁₋₄ alkyl, may beprepared in an analogous manner to that of a compound of formula (VI)employing appropriate reaction conditions as described by illustrationherein above from a suitable monoalkylmalonate, wherein R¹ is C₁₋₄alkyl, W is hydrogen or a halogen, preferably bromide, and R⁵ is C₁₋₆alkyl, from a compound of formula (III).

In Scheme 2, for example, the oxidant is manganese(III) agent such asmanganese(III) triacetate, or Cerium(IV) agent such as ammoniumCerium(IV) nitrate and Cerium(IV) sulfate.

Scheme 3:

In another embodiment, a compound of formula (VIII) is readilyaccessible from the appropriate 2-aminocinnamic acid ester (IX) whereinB is a suitable protecting group, for example, methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl,phenylsulfonyl, p-toluenesulfonyl, methanesulfonyl,trifluoromethanesulfonyl, methanesulfonyl or trifluoromethanesulfonyl(preferably phenylsulfonyl, p-toluenesulfonyl, methanesulfonyl ortrifluoromethanesulfonyl).

In Scheme 3, the requisite 2-aminocinnamic acid ester (IX) is reactedwith a compound of formula (XI), wherein Q is as defined above and E ishalogen, preferably, iodo, bromo or chloro, in the presence of asuitable base. A suitable base is, for example, an alkali or alkalineearth metal alkoxide, carbonate, fluoride or hydride, such as sodiumtert-butoxide, potassium tert-butoxide, sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydride, potassium fluoride orpotassium hydride. Preferred reaction inert solvents include, but arenot limited to, acetone, methyl ethyl ketone, acetonitrile,N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA),dimethylsulfoxide (DMSO), dioxane or tetrahydrofuran (THF). Reactiontemperatures are preferably in the range of −40° C. to refluxtemperature of solvent (for example 200° C.), usually in the range of 0°C. to 100° C., but if necessary, lower or higher temperature can beemployed. Reaction time is in general from 2 minutes to a day,preferably from 30 minutes to 8 hours, however shorter or longerreaction times, if necessary, can be employed. When the reaction is, forexample, conducted at room temperature (e.g., 25° C.) the intermediateindoline (X) can be isolated. Reaction at higher temperatures (e.g., 40to 100° C.) can result in formation of indole (XII). Usually theintermediate indoline (X) is not isolated but either (i) hydrolyzed withcommitant formation of the indole ring directly to a compound of formula(VIII) under standard conditions known to those skilled in the art, or(ii) transformed to a compound of formula (XII) by using a suitablebase, for example, an alkali or alkaline earth metal carbonate such assodium carbonate, potassium carbonate or cesium carbonate, or an organicbase such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane(DABCO), pyridine, pyrrolidine, triethylamine, diisopropylamine,diisopropylethylamine, diethylisopropylamine, Hunig's base, potassiumtert-butoxide, sodium tert-butoxide, or the like, or a suitable oxidantsuch as cerium(IV) ammonium nitrate (CAN), manganese(IV) oxide,manganese(III) triacetate, copper(II) acetate/air, chloranil,2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),N-methylmorpholine-N-oxide, or the like (for example, see H. Dumoulin etal; J. Heterocycl. Chem., 32, 1703, 1995; H. Rapoport et al; TetrahedronLett., 5053, 1991; P. Martin et al; Helv. Chim. Acta, 77, 111, 1994; Y.Kikugawa et al, J. Chem. Soc. Perkins Trans 1, 7, 1401, 1984; A. Goti etal; Tetrahedron Lett., 6567, 1996; L. S. Liebeskind et al; J. Org. Chem,61, 2594, 1996). Preferred reaction inert solvents include, but are notlimited to, acetone, methyl ethyl ketone, acetonitrile, dioxane ortetrahydrofuran (THF). Reaction temperatures are preferably in the rangeof 0° C. to reflux temperature of solvent, usually in the range of 15 to60° C., but if necessary, lower or higher temperature can be employed.Reaction time is in general from several minutes to a day, preferablyfrom 30 minutes to 8 hours, however shorter or longer reaction times, ifnecessary, can be employed. A compound of formula (XII) may be readilyhydrolyzed to a compound of formula (VIII) under standard conditions.

Scheme 4:

In another embodiment, a compound of formula (VIII), wherein Q, X, R¹and n are as defined above, may be prepared as illustrated in Scheme 4.

For example, treatment of a compound of formula (XIII), wherein R¹, R⁵,X and n are as defined above, with a trialkyltin hydride, e.g.,tributyltin hydride usually in the presence of a radical initiator suchas, 2,2′-azabisisobutyronitrile (AIBN), affords the intermediate2-stannylindole (XIV) via an intramolecular radical cyclization asdescribed in J. Am. Chem. Soc., 116, 3127, (1994); T. Fukuyama et al.The intermediate (XIV) generated in situ is subsequently treated with anacyl halide, wherein Q and E are as defined above, in the presence of asuitable palladium catalyst according to Stille's procedure (for examplesee. J. K. Stille et al; J. Am. Chem. Soc., 109, 813, 5478, (1987) andJ. Am. Chem. Soc., 106, 4833, (1984)) to afford indole (XII) which maybe hydrolyzed to a compound of formula (VIII) by conventional procedure.

Examples of the palladium catalyst are

tetrakis(triphenylphosphine)palladium(0),

dichlorobis(triphenylphosphine)palladium(II),

bis(dibenzylideneacetone)palladium(0),

benzyl(chloro)bis(triphenylphosphine)palladium(II),

bis(acetonitrile)dichloropalladium(II).

Scheme 5:

In another embodiment, a compound of formula (VIII), wherein Q, X, R¹and n are as defined above, may be prepared as illustrated in Scheme 5.

For example, treatment of a compound (XV), wherein R¹, X and n are asdefined above, is reacted with a compound of formula Q—C(O)—A affords acompound of formula (VIII), or a compound of formula (XVI) (for examplesee U. Pindur et al., Liebigs Ann. Chem., 601 (1991) and C. J. Moody etal., J. Chem. Soc. Perkin Trans. I, 3249 (1988)) which may be hydrolyzedto a compound of formula (VIII) by conventional procedure (for examplesee E. B. Fray et al., Tetrahedron, 49, 439 (1993) and U. Pindur et al.,J. Heterocycl. Chem., 29, 145 (1992)). In a compound of formulaA—C(O)—Q, A is defined such that the compound of A—C(O)—Q is, forexample, an acyl halide, carboxylic acid, carboxylic acid anhydride, amixed carboxylic sulfonic anhydride, or the like. The reaction may beconducted in the presence or absence of catalyst, preferably in thepresence of catalyst such as, boron trifluoride-diethyl ether, tin(IV)chloride, aluminum chloride, ferric chloride, zinc chloride, iodine,iron, or the like. Preferred reaction inert solvents include, but arenot limited to, diethyl ether, dichloromethane, 1,2-dichloroethane,carbon disulfide, nitrobenzene or nitromethane. Reaction temperaturesare preferably in the range of −78 to 210° C., usually in the range of−10° C. to reflux temperature of solvent, but if necessary, lower orhigher temperature can be employed. Reaction time is in general fromseveral minutes to a day, preferably from 30 minutes to 8 hours, howevershorter or longer reaction times, if necessary, can be employed.

Scheme 6:

Acetic acid compounds of formulae (VI) and (VIII) as described in theaforementioned schemes may be readily transformed to the correspondingamide, compounds of formulae (XVII) and (XVIII), or ester, compound offormula (XII), by any conventional method known to those skilled in theart.

As depicted in Scheme 6, compounds of formulae (XVII) and (XVIII) can bereadily prepared by treating the requisite acetic acid compounds offormulae (VI) and (VIII) with an appropriate amine, wherein R², R³, Yand r are as described herein before, in the presence of a suitablecoupling reagent such as, but not limited to,1-(dimethylaminopropyl)-3-ethylcarbodiimide (WSC),N,N′-dicyclohexylcarbodiimidazole (DCC), carbonyldiimidazole,diethylphosphorocyanidate (DEPC), or the like. Preferred reaction inertsolvents include, but are not limited to, acetone, acetonitrile,dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), dioxane,tetrahydrofuran (THF) or pyridine. Reaction temperatures are preferablyin the range of 40 to 150° C., usually in the range of 15° C. to refluxtemperature of solvent, but if necessary, lower or higher temperaturecan be employed. Reaction time is in general from several minutes to aday, preferably from 30 minutes to 8 hours, however shorter or longerreaction times, if necessary, can be employed. The compounds of formulae(VI) and (VIII) can also be readily transformed to the correspondingester by conventional methods.

(wherein B is a suitable protecting group, R⁵ is C₁₋₆ alkyl, E is halo,Q, X and n is as defined above.)

In Scheme 7, the starting material of formula 7-I may be preparedaccording to methods familiar to those of ordinary skill in the art,including one or more synthetic procedures described in R. W. Carling,P. D. Leeson, K. Moore, J. D. Smith, C. R. Moyes, J. Med. Chem., 1993,pages 3397-3408.

The compound of formula 7-II is prepared from a compound of formula 7-Iby treatment with a base and an electrophile in a suitable solvent.Suitable bases include such as triethylamine, diisopropylethylamine, orpyridine optionally substituted by 1 to 3 (C₁-C₄)alkyl groups,preferably pyridine. Suitable electrophiles include methanesulfonylchloride or anhydride, or phenylsulfonyl chloride wherein the phenylmoiety of said phenylsulfonyl optionally includes 1 or 2 substituentsselected from halo, nitro, and (C₁-C₄)alkyl. Suitable solvents includedichloromethane, dichloroethane, methyl t-butyl ether, disopropyl etheror toluene, preferably dichloromethane. The temperature of the aforesaidreaction may range from about 0° C. to about 50° C., preferably aboutroom temperature (20-25° C.) for a period of about 1 to 30 hours,preferably about 18 hours.

The compound of formula 7-IV is prepared from a compound of formula 7-IIby treatment with a first base and an alkylating agent of the formula7-III in the presence of a solvent followed by reaction with a secondbase followed by reaction with an acid. Suitable first bases includepotassium carbonate, potassium bicarbonate, sodium bicarbonate, sodiumcarbonate or cesium carbonate, preferably potassium carbonate. Suitablesolvents include N,N-dimethylacetamide, N,N-dimethylformamide, methylethyl ketone, acetone or tetrahydrofuran, preferablyN,N-dimethylaetamide. The aforesaid reaction is performed at atemperature ranging from about 0° C. to about 100° C., preferably roomtemperature (20-25° C.), for a period of time of about 10 minutes to 5hours, typically 15 minutes. Suitable second bases include an aqueoussolution of a base such as sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium t-pentoxide (followed by water),sodium methoxide (followed by water) or potassium t-butoxide (followedby water), preferably sodium hydroxide. The reaction with the secondbase is performed at a temperature ranging from about 20° C. to about120° C., preferably 100° C., for a period of time of about 1 hour to 24hours, typically 8 hours. Suitable acids include aqueous hydrochloricacid, hydrobromic acid, sulfuric acid or ammonium chloride, preferablyhydrochloric acid. The reaction with the acid is performed at atemperature ranging from about 0° C. to about 50° C., preferably about20° C. to about 25° C., for a period of time of about ½ hour to about 6hours, typically about 1 hour.

Alternatively, the conversion of the compound of formula 7-II to acompound of formula 7-IV can be accomplished stepwise. The compound offormula 7-V may be prepared from a compound of formula 7-II by treatmentwith a base and an alkylating agent of formula 7-III in the presence ofa solvent. Suitable bases include potassium carbonate, potassiumbicarbonate, sodium bicarbonate, sodium carbonate, or cesium carbonate,preferably potassium carbonate. Suitable solvents includeN,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone,acetone or tetrahydrofuran, preferably N,N-dimethylacetamide. Thetemperature for the aforesaid reaction may range from about 0° C. toabout 50° C., preferably room temperature (20-25° C.), for a period oftime of about 10 minutes to 40 minutes, typically 30 minutes.

The compound of formula 7-VI is prepared from a compound of formula 7-Vby reaction with a base in the presence of a solvent. Suitable basesinclude potassium carbonate, potassium bicarbonate, sodium bicarbonate,sodium carbonate or cesium carbonate, preferably potassium carbonate.Suitable solvents include N,N-dimethylacetamide, N,N-dimethylformamide,methyl ethyl ketone, acetone or tetrahydrofuran, preferablyN,N-dimethylacetamide. The temperature for the aforesaid reaction mayrange from about 0° C. to about 50° C., preferably room temperature(20-25° C.), for a period of time of about 1 hour to 6 hours, preferably4 hours.

The compound of formula 7-VII is prepared from a compound of formula7-VI by reaction with a base in a suitable solvent. Suitable basesinclude 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-ene, 1,1,3,3-tetramethylguanidine, sodiumt-pentoxide, sodium methoxide or potassium t-butoxide, preferably1,8-diazabicyclo[5.4.0]undec-7-ene methoxide or potassium t-butoxide.Suitable solvents include N,N-dimethylacetamide, N,N-dimethylformamide,methyl ethyl ketone, acetone or tetrahydrofuran, preferablyN,N-dimethylacetamide. The temperature for the aforesaid reaction mayrange from about 0° C. to 100° C., preferably room temperature (20-25°C.), for a period of 30 minutes to 5 hours, preferably 1 hour.

The compound of formula 7-IV is prepared from a compound of formula7-VII by treatment with a base in a suitable solvent. Suitable basesinclude sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodiumt-pentoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide,preferably sodium hydroxide. Suitable solvents include an aqueousmixture of methanol, ethanol, isopropyl alcohol or tetrahydrofuran,preferably methanol, containing water. The temperature of the aforesaidreaction may range from about 10° C. to 100° C., preferably roomtemperature (20-25° C.), for a period of 12 to 48 hours, preferably 24hours, to provide the carboxylate salt of compound of formula 7-IV whichcan then be treated with an acid to provide the compound of formula7-IV.

The compound of formula 7-VI has asymmetric atoms and therefore exist indifferent enantiomeric and diastereomeric forms. Diastereomeric mixturescan be separated into their individual diastereomers on the basis oftheir physical chemical differences by methods known to those skilled inthe art, for example, by chromatography or fractional crystallization.The use of all such isomers, including diastereoisomer mixtures and pureenantiomers, are considered to be part of the present invention.

The starting materials in the aforementioned general syntheses may beobtained by conventional methods known to those skilled in the art. Thepreparation of such starting materials is described within theaccompanying non-limiting examples which are provided for the purpose ofillustration only. Alternatively, requisite starting materials may beobtained by analogous procedures, or modifications thereof, to thosedescribed hereinafter.

The products which are addressed in the aforementioned general synthesesand illustrated in the experimental examples described herein after maybe isolated by standard methods and purification can be achieved byconventional means known to those skilled in the art, such asdistillation, crystallization or chromatography techniques.

Certain compounds described herein contain one or more asymmetriccenters and are capable of existing in various stereoisomeric forms. Thepresent invention contemplates all such possible stereoisomers as wellas their racemic and resolved, enantiomerically pure forms andpharmaceutically acceptable salts thereof Certain compounds of thepresent invention are capable of forming addition salts with inorganicor organic acids. The pharmaceutically acceptable acid salts of thecompounds of formula (I) are those which form non-toxic addition salts,such as, but not limited to, the hydrochloride, hydrobromide, sulfate orbisulfate, acetate, benzoate, besylate, citrate, fumarate, glucuronate,hippurate, lactate, tartrate, saccharate, succinate, maleate,methanesulfonate, p-toluenesulfonate, phosphate and pamoate (i.e.,4,4′-methylene-bis-(3-hydroxy-2-naphthoate)) salts. The pharmaceuticallyacceptable acid salts may be prepared by conventional techniques.

Certain compounds of the present invention are capable of formingpharmaceutically acceptable non-toxic cations. Pharmaceuticallyacceptable non-toxic cations of compounds of formula (I) may be preparedby conventional techniques by, for example, contacting said compoundwith a stoichiometric amount of an appropriate alkali or alkaline earthmetal (sodium, potassium, calcium and magnesium) hydroxide or alkoxidein water or an appropriate organic solvent such as ethanol, isopropanol,mixtures thereof, or the like.

Also included within the scope of this invention are bioprecursors (alsocalled pro-drugs) of the compounds of the formula (I). A bioprecursor ofa compound of the formula (I) is a chemical derivative thereof which isreadily converted back into the parent compound of the formula (I) inbiological systems. In particular, a bioprecursor of a compound of theformula (I) is converted back to the parent compound of the formula (I)after the bioprecursor has been administered to, and absorbed by, amammalian subject, e.g., a human subject. When the compounds of theformula (I) of this invention may form solvates such as hydrates, suchsolvates are included within the scope of this invention.

An example of prodrug of the compound of formula (I) is a compound ofthe formula (I), wherein the 1st position of indole ring is substitutedwith a group selected from hydroxymethyl, —C(O)—C₁₋₄ alkyl,—C(O)—(NH₂)CH—(C₁₋₄ alkyl), —C(O)-phenyl, —CH₂NHC(O)-aryl, —CH₂—C₁₋₄alkyl-O—C(O)—C₁₋₄ alkyl, —C₁₋₄ alkyl-pyridyl, —C(O)CH₂NR₂ and —CH₂N(C₁₋₄alkyl)₂.

Another example of prodrug of the compound of formula (I) is a compoundof the formula (I), wherein the carboxyl group is substituted with agroup selected from C₁₋₄ alkyl, —CH₂—C₁₋₄ alkyl-O—C(O)—C₁₋₄ alkyl,—CH₂—C₁₋₄alkyl-O—C(O)—N(C₁₋₄ alkyl)₂, —CH₂C(O)—N(C₁₋₄ alkyl)₂, —CH₂—C₁₋₄alkyl-O—C(O)—O—C₁₋₄alkyl, ethyl-OH and —CH₂CO₂H.

The compounds of the formula (I) of this invention can be administeredvia either the oral, parenteral or topical routes to mammals. Ingeneral, these compounds are most desirably administered to humans indoses ranging from 0.01 mg to 100 mg per kg of body weight per day,although variations will necessarily occur depending upon the weight,sex and condition of the subject being treated, the disease state beingtreated and the particular route of administration chosen. However, adosage level that is in the range of from 0.01 mg to 10 mg per kg ofbody weight per day, single or divided dosage is most desirably employedin humans for the treatment of abovementioned diseases.

The compounds of the present invention may be administered alone or incombination with pharmaceutically acceptable carriers or diluents byeither of the above routes previously indicated, and such administrationcan be carried out in single or multiple doses. More particularly, thenovel therapeutic agents of the invention can be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, trochees, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored.In general, the therapeutically-effective compounds of this inventionare present in such dosage forms at concentration levels ranging 5% to70% by weight, preferably 10% to 50% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate,dipotassium phosphate and glycine may be employed along with variousdisintegrants such as starch and preferably corn, potato or tapiocastarch, alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatine capsules; preferred materials in this connectionalso include lactose or milk sugar as well as high molecular weightpolyethylene grycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various combinations thereof.

For parenteral administration, solutions of a compound of the presentinvention in either sesame or peanut oil or in aqueous propylene glycolmay be employed. The aqueous solutions should be suitably buffered(preferably pH>8) if necessary and the liquid diluent first renderedisotonic. These aqueous solutions are suitable for intravenous injectionpurposes. The oily solutions are suitable for intra-articular,intra-muscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well-known to those skilled in theart. Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of creams, jellies,gels, pastes, ointments and the like, in accordance with standardpharmaceutical practice.

The compounds of formula (I) may also be administered in the form ofsuppositories for rectal or vaginal administration of the activeingredient. These compositions can be prepared by mixing the activeingredient with a suitable non-irritating excipient which is solid atroom temperature (for example, 10° C. to 32° C.) but liquid at therectal temperature and will melt in the rectum or vagina to release theactive ingredient. Such materials are polyethylene glycols, cocoabutter, suppository and wax.

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

Combination With Other Drugs:

Compounds of Formula I would be useful for, but not limited to, thetreatment of inflammation in a subject, and for treatment of otherinflammation-associated disorders, such as, as an analgesic in thetreatment of pain and headaches, or as an antipyretic for the treatmentof fever. For example, combinations of the invention would be useful totreat arthritis, including but not limited to rheumatoid arthritis,spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis. Such combinations of the inventionwould be useful in the treatment of asthma, bronchitis, in menstrualcramps, tendinitis, bursitis, and skin related conditions such aspsoriasis, eczema, burns and dermatitis. Combinations of the inventionalso would be useful to treat gastrointestinal conditions such asinflammatory bowel disease. Crohn's disease, gastritis, irritable bowelsyndrome and ulcerative colitis and for the prevention of colorectalcancer. Combinations of the invention would be useful in creatinginflammation in such diseases as vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis,multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, hypersensitivity, Conjunctivitis, swellingoccurring after injury, myocardial ischemia, and the like. Thecombinations would also be useful for the treatment of certain centralnervous system disorders such as Alzheimer's disease and dimentia. Thecombinations of the invention are useful as anti-inflammatory agents,such as for the treatment of arthritis, with the additional benefit ofhaving significantly less harmful side effects. These compositions wouldalso be useful in the treatment of allergic rhinitis, respiratorydistress syndrome, endotoxin shock syndrome, atherosclerosis and centralnervous system damage resulting from stroke, ischemia and trauma.

Compounds of formula (I) will be useful as a partial or completesubstitute for conventional NSAID's in preparations wherein they arepresently co-administered with other agents or ingredients. Thus, theinvention encompasses pharmaceutical compositions for treating COX-2mediated diseases as defined above comprising a non-toxictherapeutically effective amount of the compound of formula (I) and oneor more ingredients such as another pain reliever includingacetaminophen or phenacetin; a potentiator including caffeine; anH₂-antagonist, aluminom or magnesium hydroxide, simethicone, adecongestant including phenylephrine, phenylproanolamine,psuedophedrine, oxymetazoline, ephinephrine, naphazoline,xylometazoline, propylhexedrine, or levodesoxyephedrine; an antiitussiveincluding codeine, hydrocodone, caramiphen, carbetapentane, ordextramethorphan; a prostaglandin including misoprostol, enprostil,rioprostil, ornoprotol or rosaprostol; a diuretic; a sedating ornon-sedating antihistamine; anticancer agents such as angiostatin andendostatin; anti-Alzheimers such as Doepezil and Tacrine hydrochloride;and TNF alpha inhibitors such as Etanercept.

These cyclooxygenase inhibitors can further be used in combination witha nitric oxide inhibitors disclosed in WO 96/28145.

Also, the invention encompasses pharmaceutical compositions for treatingCOX-2 mediated diseases as defined above comprising a non-toxictherapeutically effective amount of the compound of formula (I) and oneor more anti-ulcer agent and/or prostaglandins, which are disclosed inWO 97/11701.

The useful prostaglandins include misoprostol, plus-minus methyl11α,16-dihydroxy-16-methyl-9-oxoprost 13E-en-1-oate; enisoprost andmethyl-7-[2B-[6-(1-cyclopenten-1-yl)-4-hydroxy-4-methyl-1E,5E-hexadienyl]-3α-hydroxy-5-oxo 1R,1α-cyclopentyl]-4Z-heptenoate.Prostaglandins within the scope of the invention also includearbaprostil, enprostil, rioprostol, nocloprost, mexiprostil,ornoprostol, dimoxaprost, tiprostanide and rosaprostol.

The present compounds may also be used in co-therapies, partially orcompletely, in place of other conventional antiinflammatories, such astogether with steroids, 5-lipoxygenase inhibitors, LTB₄ antagonists andLTA₄ hydrolase inhibitor's.

An example of LTB₄ is disclosed in WO97/29774. Suitable LTB₄ inhibitorsinclude, among others, ebselen, Bayer Bay-x-1005, Ciba Geigy compoundCGS-25019C, Leo Denmark compound ETH-615, Lilly compound LY-293111, Onocompound ONO4057, Terumo compound TMK-688, Lilly compounds LY-213024,264086 and 292728, Ono compound ONO-LB457, Searle compound SC-S3228,calcitrol, Lilly compounds LY-210073, LY223982, LY233469, and LY255283,Ono compound ONO-LB-448, Searle compounds SC-41930, SC-50605 andSC-51146, and SK&F compound SKF-104493. Preferably, the LTB₄ inhibitorsare selected from ebselen, Bayer Bay-x-1005, Ciba Geigy compoundCGS-25019C, Leo Denmark compound ETH-61S, Lilly compound LY-293111, Onocompound ONO-4057 and Terumo compound TMK-688.

An example of 5-LO inhibitors is disclosed in WO97/29776. Suitable 5-LOinhibitors include, among others, masoprocol, tenidap, zileuton,pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadremphosphate and bunaprolast.

An example of LTA₄ hydrolase inhibitors is disclosed in WO97/29774.Suitable LTA₄ hydrolase inhibitors include, among others, Rhone-PoulencRorer RP-64966.

The administration of the present invention may be for either preventionor treatment purposes. The methods and compositions used herein may beused alone or in conjunction with additional therapies known to thoseskilled in the art in the prevention or treatment of angiogenesis.Alternatively, the methods and compositions described herein may be usedas adjunct therapy. By way of example, the cyclooxygenase-2 inhibitormay be administered alone or in conjunction with other antineoplasticagents or other growth inhibiting agents or other drugs or nutrients.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which couldbe selected for treatment of angiogenesis by combination drugchemotherapy. Such antineoplastic agents fall into several majorcategories, namely, antibiotic-type agents, alkylating agents,antimetabolite agents, hormonal agents, immunological agents,interferon-type agents and a category of miscellaneous agents.Alternatively, other anti-neoplalstic agents, such as metallomatrixproteases inhibitors (MMP), such as MMP-13 inhibitors includingbatiastat, marimastat. Agouron Pharmaceuticals AG-3340, and RocheR0-32-3555, or alpha,beta,inhibitors may be used.

A first family of antineoplastic agents which may be used in combinationwith a selective cyclooxygenase-2 inhibitor consists ofantimetabolite-type antineoplastic agents. Suitable antimetaboliteantineoplastic agents may be selected from the group consisting of5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium,carmoftir, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabinephosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku F0-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES. norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT anduricytin.

A second family of antineoplastic agents which may be used incombination with a selective cyclooxygenase-2 inhibitor consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from the group consisting ofShionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone,Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102,carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil,cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233,cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine,diplatinum cytostatic. Erba distamycin derivatives, Chugai DWA-2114R,ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium,fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide,iproplatin, lomustine, mafosfamnide, mitolactol, Nippon Kayaku NK-121,NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine,Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, YakultHonsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine,temozolomide, teroxirone, tetraplatin and trimelamol.

A third family of antineoplastic agents which may be used in combinationwith a selective cyclooxygenase-2 inhibitor consists of antibiotic-typeantineoplastic agents. Suitable antibiotic-type antineoplastic agentsmay be selected from the group consisting of Taiho 4181-A, aclarubicin,actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative,Ajinomoto AN-201-II. Ajinomoto AN-3, Nippon Soda anisomycins,anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859,Bristol-Myers BMY-25067. Bristol-Myers BMY-25551, Bristol-MyersBMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycinsulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, KyowaHakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakcko DC92-B, ditrisarubicinB, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A,epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b.Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482,glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins,kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602,Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, AmericanCyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin,mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, NipponKayaku NKT-O1, SRI International NSC-357704, oxalysine, oxaunomycin,peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, TobishiRA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin,Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSPharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin,Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975,Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-2S024 andzorubicin.

A fourth family of antineoplastic agents which may be used incombination with the selective cyclooxygenase-2 inhibitor consists of amiscellaneous family of antineoplastic agents selected from the groupconsisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile.arnsacrine, Angiostat, ankinomycin, anti-neoplaston AIO, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene.Bristo-Myers BMY-40481, Vestar boron-1O, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-1OO,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmnar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate,Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, FujisawaFR-57704, gallium nitrate, genkwadaphnin, Chugai GLA43, Glaxo GR-63178,grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221,homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine,isotretinoin. Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, KurehaChemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin,lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin,Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyaninederivatives, methylanilinoacridine, Molecular Genetics MGI-136,minactivin, mitonafide, mitoquidone, mopidamol, motretinide, ZenyakuKogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, octreotide, Ono ON0-112, oquizanocine, Akzo Org-10172,pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-LambertPD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1OO1, ICRT peptideD, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin,probimane, procarbazine, proglurnide, Invitron protease nexin I, TobishiRA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine,retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976,SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharmSP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed,SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237,Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680,taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29,tocotrienol, Topostin, Teijin TT-82, kyowa Hakko UCN-O1, Kyowa HakkoUCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate,vincristine, vindesine, vinestramide, vinorelbine, vintriptol,vinzolidine, withanolides and Yamanouchi YM-534.

Examples of radioprotective agents which may be used in the combinationchemotherapy of this invention are AD-5, adchnon, amifostine analogues,detox, dimesna, 1-102, MN-159, N-acylated-dehydroalanines,TGF-Genentech, tiprotimod, amifostine, WR-1511327, FUT-187, ketoprofentransdermal, naburnetone, superoxide dismutase (Chiron) and superoxidedisrrtutase Enzon.

Methods for preparation of the antineoplastic agents described above maybe found in the literature. Methods for preparation of doxorubicin, forexample, are described in U.S. Pat. Nos. 3,590,028 and No. 4,012,448.Methods for preparing metallomatrix protease inhibitors are described inEP 780386, WO97/20824. WO96/15096. Methods for preparing SOD mimics aredescribed in EP 524,101. Methods for preparing alpha,beta, inhibitorsare described in WO97/08174.

In addition, the selective COX-2 inhibitor may be administered inconjunction with other antiinflammatory agents for maximum safety andefficacy, including NSAID's, selective COX-1 inhibitors and inhibitorsof the leukotriene pathway, including 5-lipoxygenase inhibitors.Examples of NSAID's include indomethacin, naproxen, ibruprofen,salicylic acid derivatives such as aspirin, diclofenac, ketorolac,piroxicam, meloxicam, mefenamic acid, sulindac, tolmetin sodium,zomepirac, fenoprofen, phenylbutazone, oxyphenbutazone, nimesulide,zaltoprofen and letodolac.

Method for Assessing Biological Activities

The activity of the compounds of the formula (I) of the presentinvention was demonstrated by the following assays.

In Vitro Assays

Human Cell Based COX-1 Assay

Human peripheral blood obtained from healthy volunteers was diluted to1/10 volume with 3.8% sodium citrate solution. The platelet-rich plasmaimmediately obtained was washed with 0.14 M sodium chloride containing12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA. Platelets were then washed withplatelet buffer (Hanks buffer (Ca free) containing 0.2% BSA and 20 mMHepes). Finally, the human washed platelets (HWP) were suspended inplatelet buffer at the concentration of 2.85×10⁸ cells/ml and stored atroom temperature until use. The HWP suspension (70 μl aliquots, final2.0×10⁷ cells/ml) was placed in a 96-well U bottom plate and 10 μlaliquots of 12.6 mM CaCl₂ added. Platelets were incubated with A23187(final 10 μM, Sigma) with test compound (0.1-100 μM) dissolved in DMSO(final concentration; less than 0.01%) at 37° C. for 15 min. Thereaction was stopped by addition of EDTA (final 7.7 mM) and TxB₂ in thesupernatant quantitated by using a radioimmunoassay kit (Amersham)according to the manufacturer's procedure.

Human Cell Based COX-2 Assay

Inhibition of COX-2 Activity After Induction of COX-2 by hIL-1β

The human cell based COX-2 assay was carried out as previously described(Moore et al., Inflam. Res., 45, 54, 1996). Confluent human umbilicalvein endothelial cells (HUVECs, Morinaga) in a 96-well U bottom platewere washed with 100 μl of RPMI1640 containing 2% FCS and incubated withhIL-1β (final concentration 300 U/ml, R & D Systems) at 37° C. for 24hr. After washing, the activated HUVECs were stimulated with A23187(final concentration 30 μM) in Hanks buffer containing 0.2% BSA, 20 mMHepes and test compound (0.1 nM-100 μM) dissolved in DMSO (finalconcentration; less than 0.01%) at 37° C. for 15 min. 6-Keto-PGF_(1α),stable metabolite of PGI₂, in the supernatant was quantitated afteradequate dilution by using a radioimmunoassay kit (Amersham) accordingto the manufacturer's procedure.

Inhibition of COX-2 During the Induction Phase

Confluent human umbilical vein endothelial cells (HUVECs, Morinaga) in a96-well U bottom plate were washed with 100 μl of RPMI1640 containing 2%FCS and test compound (0.1 nM-100 μM) dissolved in DMSO (finalconcentration; less than 0.01%), and incubated with hIL-1β (finalconcentration 300 U/ml, R & D Systems) at 37° C. for 24 hr. Afterwashing, the HUVECs were stimulated with A23187 (final concentration 30μM) in Hanks buffer containing 0.2% BSA and 20 mM Hepes at 37° C. for 15min. 6-Keto-PGF_(1α), a stable metabolite of PGI₂, in the supernatantwas quantitated after adequate dilution by using a radioimmunoassay kit(Amersham) according to the manufacturer's procedure.

In Vivo Assays

Carrageenan Induced Foot Edema in Rats

Male Sprague-Dawley rats (5 weeks old, Charles River Japan) were fastedovernight. A line was drawn using a marker above the ankle on the righthind paw and the paw volume (V0) was measured by water displacementusing a plethysmometer (Muromachi). Animals were given orally eithervehicle (0.1% methyl cellulose or 5% Tween 80) or a test compound (2.5ml per 100 g body weight). One hour later, the animals were theninjected intradermally with λ-carrageenan (0.1 ml of 1% w/v suspensionin saline, Zushikagaku) into right hind paw (Winter et al., Proc. Soc.Exp. Biol. Med., 111, 544, 1962; Lombardino et al., Arzneim. Forsch.,25, 1629, 1975) and three hours later, the paw volume (V3) was measuredand the increase in volume (V3-V0) calculated. Since maximum inhibitionattainable with classical NSAIDs is 60-70%, ED30 values were calculated.

Gastric Ulceration in Rats

The gastric ulcerogenicity of test compound was assessed by amodification of the conventional method (Ezer et al., J. Pharm.Pharmacol., 28, 655, 1976; Cashin et al., J. Pharm. Pharmacol., 29,330-336, 1977). Male Sprague-Dawley rats (5 weeks old, Charles RiverJapan), fasted overnight, were given orally either vehicle (0.1% methylcellulose or 5% Tween 80) or a test compound (1 ml per 100 g bodyweight). Six hours after, the animals were sacrificed by cervicaldislocation. The stomachs were removed and inflated with 1% formalinsolution (10 ml). Stomachs were opened by cutting along the greatercurvature. From the number of rats that showed at least one gastriculcer or haemorrhaging erosion (including ecchymosis), the incidence ofulceration was calculated. Animals did not have access to either food orwater during the experiment.

Data Analysis

Statistical program packages, SYSTAT (SYSTAT, INC.) and StatView (AbacusCencepts, Inc.) for Macintosh were used. Differences between testcompound treated group and control group were tested for using ANOVA.The IC₅₀ (ED₃₀) values were calculated from the equation for thelog-linear regression line of concentration (dose) versus percentinhibition.

Some compounds prepared in the Working Examples as described hereinafter were tested by these methods, and showed IC₅₀ values of 0.001 μMto 10 μM with respect to inhibition of COX-2.

Also, the above-mentioned most preferred compounds were tested by thesemethods, and showed IC₅₀ values of 0.001 μM to 0.5 μM with respect toinhibition of COX-2.

COX-2 selectivity can be determined by ratio in terms of IC₅₀ value ofCOX-1 inhibition to COX-2 inhibition. In general, it can be said that acompound showing a COX-1/COX-2 inhibition ratio of more than 2 has goodCOX-2 selectivity.

Some compounds prepared in Examples showed COX-1/COX-2 inhibition ratioof more than 10.

The following examples contain detailed descriptions of the methods ofthe preparation of compounds of formula (I). These detailed descriptionsfall within the scope of the invention and serve to exemplify the abovedescribed general synthetic procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended to restrict the scope of the present invention.

EXAMPLES

The invention is illustrated in the following non-limiting examples inwhich, unless stated otherwise: all operations were carried out at roomor ambient temperature, that is, in the range of 18-25° C.; evaporationof solvent was carried out using a rotary evaporator under reducedpressure with a bath of up to 60° C.; reactions were monitored by thinlayer chromatography (tlc) and reaction times are given for illustrationonly; melting points (m.p.) given are uncorrected (polymorphism mayresult in different melting points); structure and purity of allisolated compounds were assured by at least one of the followingtechniques: tlc (Merck silica gel 60 F-254 precoated plates), massspectrometry, nuclear magnetic resonance (NMR) or microanalysis. Yieldsare given for illustrative purposes only. Flash column chromatographywas carried out using Merck silica gel 60 (230-400 mesh ASTM).Low-resolution mass spectral data (EI) were obtained on a Automass 120(JEOL) mass spectrometer. Low-resolution mass spectral data (ESI) wereobtained on a Quattro II (Micromass) mass spectrometer. NMR data wasdetermined at 270 MHz (JEOL JNM-LA 270 spectrometer) using deuteratedchloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unlessindicated otherwise, relative to tetramethylsilane (TMS) as internalstandard in parts per million (ppm); conventional abbreviations usedare: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad,etc.

Example 1 Ethyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate

Step 1. Ethyl trans-4-Chloro-2-nitrocinnamate

To a suspension of sodium hydride (60% w/w dispersion in mineral oil,4.4 g, 0.11 mol) in THF (150 ml) was added dropwise a solution oftriethyl phosphonoacetate (25.0 g, 0.11 mol) in THF (50 ml) at roomtemperature. After stirring for 1 h. a solution of4-chloro-2-nitrobenzaldehyde (19.0 g, 0.10 mol) in THF (50 ml) wasadded. After stirring for an additional 1 h, saturated aqueous ammoniumchloride (50 ml) was added and the resulting mixture was extracted withethyl acetate (300 ml×2). The combined organic extracts were dried(MgSO₄) and concentrated to gave 27 g (quant.) of the title compound asbrown solids.

¹H-NMR (CDCl₃) δ: 8.04 (1H, d, J=15.8 Hz), 8.03 (1H, d, J=1.8 Hz),7.64-7.58 (2H, m), 6.36 (1H, d, J=15.8 Hz), 4.30 (2H, q, J=7.0 Hz), 1.35(3H, t, J=7.0 Hz).

Step 2. Ethyl trans-2-Amino-4-chlorocinnamate

A mixture of ethyl trans-4-chloro-2-nitrocinnamate (step 1, 27.0 g, 0.11mol) and sodium hydrosulfite (92 g, 0;53 mol) in THF-H₂O (1:1, 500 ml)was stirred at room temperature for 1 h. Saturated aqueous sodiumbicarbonate (300 ml) was then added and the mixture was extracted withethyl acetate (300 ml×2). The combined organic extracts were dried(MgSO₄) and concentrated to gave 16.7 g (67%) of the title compound asyellow solids.

¹H-NMR (CDCl₃) δ: 7.72 (1H, d, J=15.8 Hz), 7.27 (1H, d, J=8.4 Hz),6.78-6.68 (2H, m), 6.31 (1H, d, J=15.8 Hz), 4.27 (2H, q, J=7.0 Hz), 1.33(3H, t, J=7.0 Hz).

Step 3. Ethyl trans-4-Chloro-2-formamidocinnamate

A mixture of acetic anhydride (20 ml) and formic acid (10 ml) was heatedat 60° C. for 2 h. After cooling to 0° C., a solution of ethyltrans-2-amino-4-chlorocinnamate (step 2, 15.5 g, 0.069 mol) in THF (80ml) was carefully added. The resulting mixture was allowed to warm toroom temperature. After stirring overnight, the mixture was concentratedand the precipitates were collected by filtration. The solids werewashed with hexane to give 9.6 g (55%) of the title compound.

¹H-NMR (CDCl₃) δ: 9.40-9.15 (1H, m), 8.51-8.40 (1H, m), 8.10-7.80 (2H,m), 7.60-7.47 (1H, m), 7.28-7.12 (1H, m), 6.40 (1H, d, J=15.8 Hz), 4.25(2H, q, J=7.3 Hz), 1.34 (3H, t, J=7.3 Hz).

Step 4. Ethyl trans-4-Chloro-2-isocyanocinnamate

To a solution of triphenylphosphine (5.3 g, 20 mmol) in dichloromethane(80 ml) cooled to 0° C. was added dropwise a solution of triphosgene(2.0 g, 6.7 mmol) in dichloromethane (20 ml). The ice-bath was removedand the resulting mixture stirred at room temperature for 10 min. Themixture was then cooled to 0° C. and a solution of ethyltrans-4-chloro-2-formamidocinnamate (step 3, 5.2 g, 0.020 mol) indichloromethane (80 ml) was added. The mixture was allowed to warm toroom temperature overnight, and then concentrated. The residue waspartitioned between water (80 ml) and ethyl acetate (100 ml), theaqueous layer separated and extracted with ethyl acetate (100 ml). Thecombined organic extracts were dried (MgSO₄), solvent removed byevaporation and the crude product was purified by flash columnchromatography eluting with ethyl acetate/hexane (1:6) to afford 3.9 g(83%) of the title compound as white solids.

¹H-NMR (CDCl₃) δ: 7.89 (1H, d, J=16.1 Hz), 7.60 (1H, d, J=8.8 Hz), 7.45(1H, d, J=1.8 Hz), 7.42 (1H, dd, J=1.8, 8.8 Hz), 6.52 (1H, d, J=16.1Hz), 4.30 (2H, q, J=7.0 Hz), 1.35 (3H, t, J=7.0 Hz).

Step 5. Ethyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate

A mixture of ethyl trans-4-chloro-2-isocyanocinnamate (step 4, 1.2 g,5.1 mmol), tributyltin hydride (1.6 g, 5.6 mmol) and AIBN (43 mg, 0.26mmol) in acetonitrile (30 ml) was heated at 100° C. After 1 h,tetrakis(triphenylphosphine)palladium (580 mg, 0.50 mmol) and benzoylchloride (0.65 ml, 5.6 mmol) were added and the mixture was heated for afurther 17 h. The mixture was cooled and poured into 2N aqueous HCl (50ml) and extracted with diethyl ether (80 ml×2). The combined organicextracts were washed with saturated aqueous potassium fluoride (50 ml)and dried (MgSO₄). After removal of solvent, the crude product waspurified by flash column chromatography eluting with ethylacetate/hexane (1:5) to afford 0.43 g (25%) of the title compound aswhite solids.

m.p.: 160-163° C. ¹H-NMR (CDCl₃) δ: 8.94 (1H, br s), 7.82-7.75 (2H, m),7.67-7.47 (4H, m), 7.37 (1H, d, J=1.8 Hz), 7.13 (1H, dd, J=1.8, 8.4 Hz),4.11 (2H, q, J=7.3 Hz), 3.78 (2H, s), 1.22 (3H, t, J=7.3 Hz).

Example 2 (2-Benzoyl-6-chloro-1H-indol-3-yl)acetic Acid Method A

To a solution of ethyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate (Example1, 380 mg, 0.11 mmol) in ethanol (15 ml) was added 2N aqueous KOH (5ml). After heating at 80° C. for 1 h, the mixture was cooled andconcentrated, and then 2N aqueous HCl (15 ml) added carefully. Themixture was extracted with diethyl ether (50 ml×2), the combined organicextracts dried (MgSO₄) and concentrated. The residual solids wererecrystallized from ethyl acetate/hexane to afford 60 mg (17%) of thetitle compound as pale yellow solids.

m.p.: 183-186° C. IR (KBr) ν: 1700, 1610, 1520, 1425, 1330, 1000 cm⁻¹.¹H-NMR (DMSO-d₆) δ: 12.26 (1H, br s), 11.76 (1H, s), 7.77-7.66 (4H, m),7.62-7.54 (2H, m), 7.48 (1H, d, J=1.8 Hz), 7.13 (1H, dd, J=1.8, 8.7 Hz),3.80 (2H, s).

Method B

Step 1. 6-Chloro-1-(phenylsulfonyl)indole

A mixture of 6-chloroindole (Y. Watanabe et al., J. Org. Chem., 1990,55, 580, 36.2 g, 0.24 mol), tetrabutylammmonium hydrogen sulfate (8.1 g,0.024 mol) and 50% aqueous KOH (160 ml) in benzene (500 ml) was stirredat room temperature for 10 min. The mixture was then cooled to 0° C. anda solution of benzenesulfonyl chloride in benzene (20 ml) was added.After stirring at room temperature for 3 h, the mixture was poured intowater (200 ml), the organic layer separated and the aqueous layerextracted with diethyl ether (200 ml×2). The combined organic extractswere washed with brine (200 ml), dried (MgSO₄) and concentrated. Theresidual solids were washed with ethanol (100 ml×3) to give 58 g (83%)of the title compound as off-white solids.

¹H-NMR (CDCl₃) δ: 8.02 (1H, s), 7.92-7.85 (2H, m), 7.60-7.40 (5H, m),7.21 (1H, dd, J=1.8, 8.4 Hz), 6.62 (1H, d, J=3.6 Hz).

Step 2. 6-Chloro-2-benzoyl-1-(phenylsulfonyl)indole

To a stirred solution of 6-chloro-1-(phenylsulfonyl)indole (Step 1,12.58 g, 43.0 mmol) in THF (270 ml) cooled to −78° C. was added dropwisetert-butyllithium. (32 ml, 52.0 mmol, 1.64 M in n-pentane) with keepingthe internal temperature below −65° C. After stirring for 30 min. at−78° C., this solution was transferred via cannula to a solution ofbenzoyl chloride (6.0 ml, 52.0 mmol) in THF (30 ml) cooled to −78° C.The mixture was stirred for 1.5 h and then quenched with saturatedammonium chloride (200 ml) at −78° C. and allowed to warm to roomtemperature. The aqueous layer was separated and neutralized withaqueous sodium carbonate, and then extracted with ethyl acetate (50ml×2). The combined organic extracts were washed with brine (50 ml),dried (MgSO₄), and concentrated. Crystallization of the residue fromdiethyl ether/hexane (1:3) afforded the title compound as white solids(1 4.4 g, 85%).

¹H-NMR(CDCl₃) δ: 8.20-8.16 (1H, m), 8.14-8.06 (2H, m), 8.01-7.93 (2H,m), 7.66-7.47 (7H, m), 7.29 (1H, dd, J=1.7, 8.5 Hz), 6.89 (1H, J=0.7Hz).

Step 3. 2-Benzoyl-6-chloroindole

A mixture of 2-benzoyl-6-chloro-1-(phenylsulfonyl)indole (step 2, 48 g,0.12 mol) and potassium carbonate (80 g, 0.58 mol) in THF-MeOH—H₂O(4:2:1, 1100 ml) was heated at reflux temperature overnight. Afterremoval of solvent, the residue was extracted with diethyl ether (300ml×2) and dried (MgSO₄). Removal of solvent gave the crude product aspale brown solids. Recrystallization from ethyl acetate afforded 20 g(65%) of the title compound as white solids.

m.p.: 206-207° C. ¹H-NMR (CDCl₃) δ: 9.31 (1H, br s), 8.01-7.95 (2H m),7.68-7.47 (5H, m), 7.17-7.12 (2H, m).

Step 4. Diethyl α-Acetoxy-(2-benzoyl-6-chloro-1H-indol-3-yl)malonate

A mixture of 2-benzoyl-6-chloroindole (step 3, 4.0 g, 16 mmol),manganese(III) acetate dihydrate (13 g, 48 mmol), diethyl malonate (14g, 80 mmol) and sodium acetate (6.6 g, 80 mmol) in acetic acid (150 ml)was heated at 80° C. with stirring for 2h. Manganese(III) acetatedihydrate (3 g, 11 mmol) was added and heating was continued for anadditional 2 h. The mixture was cooled and brine (200 ml) was added. Theresulting mixture was extracted with diethyl ether (200 ml×2) and thecombined organic extracts dried (MgSO₄) and concentrated. The residuewas purified by flash column chromatography eluting with ethylacetate/hexane (1:3) to afford 5.2 g (69%) of the title compound asyellow solids.

m.p.: 141-144° C. ¹H-NMR (CDCl₃) δ: 8.84 (1H, br s), 7.90-7.81 (3H, m),7.66-7.58 (1H, m), 7.51-7.42 (2H, m), 7.38 (1H, d, J=1.3 Hz), 7.15 (1H,dd, J=2.0, 8.7 Hz), 4.30-4.06 (4H, m), 1.70 (3H, s), 1.30-1.58 (6H, m).

Step 5. Diethyl(2-benzoyl-6-chloro-1H-indol-3-yl)malonate

A mixture of diethylα-acetoxy-(2-benzoyl-6-chloro-1H-indol-3-yl)malonate (step 4. 5.0 g, 11mmol), trifluoroacetic acid (3.3 ml, 44 mmol) and triethylsilane (2.1ml, 13 mmol) in dichloromethane (80 ml) was heated at reflux temperaturefor 12 h and then cooled and concentrated. The resulting residue waspartitioned between saturated sodium bicarbonate (50 ml) anddichloromethane (80 ml). The aqueous layer was separated and extractedwith dichloromethane (80 ml). The combined organic extracts were dried(MgSO₄) and solvent removed. Crude product was purified by flush columnchromatography eluting with ethyl acetate/hexane (1:4) to 10 afford 4.0g (87%) of the title compound as white solids.

¹H-NMR (CDCl₃) δ: 8.93 (1H, br s), 7.81-7.70 (3H, m), 7.68-7.60 (1H, m),7.55-7.48 (2H, m), 7.32 (1H, s), 7.12 (1H, dd, J=1.8, 8.8 Hz), 5.29 (1H,s), 4.26-4.09 (4H, m), 1.21 (6H, t, J=7.1 Hz).

Step 6. (2-Benzoyl-6-chloro-1H-indol-3-yl)acetic Acid

Diethyl(2-benzoyl-6-chloro-1H-indol-3-yl)malonate (step 5, 4.4 g, 11mmol) in a mixture of ethanol (120 ml) and 2N aqueous NaOH (15 ml) washeated at reflux temperature for 1 h. The mixture was cooled andconcentrated, and the residue carefully acidified with 2N aqueous HCl(30 ml). The mixture was extracted with diethyl ether (150 ml×3), andthe combined extracts were dried (MgSO₄) and concentrated. The residualsolids were recrystallized from ethyl acetate/hexane to afford 1.1 g(30%) of the title compound as pale yellow solids.

m.p.: 183-186° C. IR (KBr) ν: 1700, 1610, 1520, 1425, 1330, 1000 cm⁻¹.¹H-NMR (DMSO-d₆) δ: 12.26 (1H, br s), 11.76 (1H, s), 7.77-7.66 (4H, m),7.62-7.54 (2H, m), 7.48 (1H, d, J=1.8 Hz), 7.13 (1H, dd, J=1.8, 8.7 Hz),3.80 (2H, s).

Example 3 (2-Benzoyl-6-chloro-1H-indol-3-yl)acetic Acid, Sodium Salt

(2-Benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2, 480 mg, 1.5mmol) in ethanol (10 ml) was treated with 2N aqueous NaOH (0.7 ml, 1.4mmol) at room temperature for 30 min. and then concentrated. The residuewas dissolved in water (10 ml) and washed with diethyl ether (15 ml×2).The aqueous layer was concentrated to afford 350 mg (68%) of the titlecompound as pale brown solids.

m.p.: 185-189° C. IR (KBr) ν: 1523, 1380, 1230, 1060, 1004, 918 cm⁻¹.¹H-NMR (DMSO-d₆) δ: 11.46 (1H, br s), 7.88-7.84 (21H, m), 7.66 (1H, d,J=8.4 Hz), 7.64-7.46 (3H, m), 7.39 (1H, d, J=1.8 Hz), 7.00 (1H, dd,J=1.8, 8.4 Hz), 3.32 (2H, s).

Example 4 [6-Chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]acetic Acid

Step 2. 6-Chloro-2-(2-methylbenzoyl)-1-(phenylsulfonyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole(step 1 of Example 2, Method B) and o-toluoyl chloride.

tlc: Rf=0.3 (ethyl acetate/hexane=1:10).

Step 2. 6-Chloro-2-(2-methylbenzoyl)indole

The title compound was prepared according to the procedure described instep 3 of Example 2 (Method B) from6-chloro-2-(2-methylbenzoyl)-1-(phenylsulfonyl)indole (step 1).

¹H-NMR (CDCl₃) δ: 9.37 (1H, br s), 7.58 (2H, d, J=8.91 Hz), 7.48 (1H,s), 7.42 (1H, dd, J=1.49, 7.75 Hz), 7.34-7.27 (2H, m), 7.12 (2H, dd,J=1.81, 8.56 Hz), 2.44 (3H, s).

Step 3. Diethylα-Acetoxy-[6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 6-chloro-2-(2-methylbenzoyl)indole(step 2).

¹H-NMR (CDCl₃) δ: 8.52 (1H, br s), 7.78 (1H, d, J=8.88 Hz), 7.48-7.13(6H, m), 4.31-4.16 (4H, m), 2.52 (3H, s), 1.96 (3H, s), 1.22 (6H, t,7.26 Hz).

Step 4. Diethyl[6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) fromdiethyl(α-acetoxy-[6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]malonate(step 3).

¹H-NMR (CDCl₃) δ: 9.0 (1H, br s), 7.73 (1H, d, J=8.88 Hz), 7.73-7.09(5H, m), 7.11 (1H, dd, J=1.97, 8.75 Hz), 4.89 (1H, s), 4.20-4.08 (4H,m), 2.35 (3H, s), 1.19 (6H, t, J=7.1 Hz).

Step 5. [6-Chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]malonate (step 4).

m.p.: 150-152° C. IR (KBr) ν: 3321, 1717, 1624, 1602, 1568, 1531, 1431,1319, 1249, 1230 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.70 (1H, s), 7.69 (2H, d,8.72 Hz), 7.51-7.31 (3H, m), 7.10 (2H, dd, J=1.97, 8.56 Hz), 3.57 (2H,s), 2.24 (3H, s).

Example 5 [6-Chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 6-Chloro-2-(3-methylbenzoyl)-1-(phenylsulfonyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole(step 1 of Example 2, Method B) and m-toluoyl chloride.

tlc: Rf=0.3 (ethyl acetate/hexane=1:10).

Step 2. 6-Chloro-2-(3-methylbenzoyl)indole

The title compound was prepared according to the procedure described instep 3 of Example 2 (Method B) from6-chloro-2-(3-methylbenzoyl)-1-(phenylsulfonyl)indole (step 1).

¹H-NMR (CDCl₃) δ: 9.37 (1H, s), 7.77 (2H, br s), 7.64 (1H, d, J=8.56Hz), 7.47-7.12 (5H, m), 2.47 (3H, s).

Step 3. Diethylα-Acetoxy-[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 6-chloro-2-(3-methylbenzoyl)indole(step 2).

¹H-NMR (CDCl₃) δ: 8.80 (1H, br s), 7.83 (1H, d, J=8.88 Hz), 7.67-7.32(5H, m), 7.16 (1H, dd, J=1.81, 8.88 Hz), 4.27-4.15 (4H, m), 2.39 (3H,s), 1.72 (3H, s), 1.29 (6H, t, J=7.26 Hz).

Step 4. Diethyl[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylac-acetoxy-[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate (step3).

¹H-NMR (CDCl₃) δ: 9.21 (1H, br s), 7.71 (1H, d, J=8.51 Hz), 7.59-7.28(5H, m), 7.10 (1H, dd, J=1.97, 8.72 Hz), 5.27 (1H, s), 4.23-4.07 (4H,m), 2.40 (3H, s), 1.21 (6H, t, J=7.1 Hz).

Step 5. [6-Chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate (step 4).

m.p.: 182-184° C. IR (KBr) ν: 3313, 1699, 1616, 1568, 1533, 1408, 1325,1265, 1203 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.75 (1H, s), 7.70 (1H, d,J=8.75),7.55-7.46 (5H, m), 7.12 (1H, dd, J=1.97, 8.72 Hz), 3.75 (2H, s), 2.39(3H, s).

Example 6 [6-Chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 6-Chloro-2-(4-methylbenzoyl)-1-(phenylsulfonyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole(step 1 of Example 2, Method B) and p-toluoyl chloride.

tlc: Rf=0.3 (ethyl acetate/hexane=1:10).

Step 2. 6-Chloro-2-(4-methylbenzoyl)indole

The title compound was prepared according to the procedure described instep 3 of Example 2 (Method B) from6-chloro-2-(4-methylbenzoyl)-1-(phenylsulfonyl)indole (step 1).

¹H-NMR (CDCl₃) δ: 9.37 (1H, br s), 7.90 (2H, d, J=8.6 Hz), 7.63 (1H, d,J=8.9 Hz), 7.48 (1H, s), 7.34 (2H, d, J=8.6 Hz), 7.16-7.10 (2H, m), 2.47(3H, s).

Step 3. Diethylα-Acetoxy-[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 6-chloro-2-(4-methylbenzoyl)indole(step 2).

¹H-NMR (CDCl₃) δ: 8.65 (1H, br s), 7.84 (1H, d, J=8.9 Hz), 7.76 (2H, d,J=8.2 Hz), 7.39-7.37 (1H, m), 7.27 (2H, d, J=8.2 Hz), 7.16 (1H, dd,J=1.8, 8.2 Hz), 4.36-4.16 (4H, m), 2.44 (3H, s), 1.72 (3H, s), 1.34-1.22(6H, m).

Step 4. Diethyl[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]malonate (step 3).

¹H-NMR (CDCl₃) δ: 8.83 (1H, br s), 7.76 (1H, d, J=8.7 Hz), 7.71 (2H, d,J=8.2 Hz), 7.39-7.36 (1H, m), 7.32 (2H, d, J=8.2 Hz), 7.14 (1H, dd,J=2.0, 8.7 Hz), 5.30 (1H, s), 4.26-4.14 (4H, m), 2.47 (3H, s), 1.22 (6H,t, J=7.1 Hz).

Step 5. [6-Chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]malonate (step 4).

m.p.: 182-184° C. IR (KBr) ν: 3321, 1705, 1616, 1602, 1566, 1529, 1431,1323, 1257, 1230 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.72 (1H, s), 7.74-7.64 (3H,m), 7.49-7.45 (1H, m), 7.39 (2H, d, J=8.1 Hz), 7.16-7.09 (1H, m), 3.81(2H, s), 2.43 (3H, s).

Example 7 [6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 6-Chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole

To a stirred suspension of 6-chloroindole-2-carboxylic acid (H. N. Rydonand J. C. Tweddle, J. Chem. Soc., 1955, 3499., 7.0 g, 36 mmol) inthionyl chloride (30 ml) was added dropwise DMF (1 ml). After stirringfor 30 min., the mixture was concentrated, and the residue was dissolvedin dichloromethane (100 ml) and cooled to 0° C. To the mixture was addedN,O-dimethylhydroxylamine hydrochloride (7.0 g, 72 mmol) and pyridine(15 ml). After stirring 2 h, the mixture was quenched with water (100ml), and extracted with dichloromethane (150 ml×2). The combined organicextracts were washed with 2N aqueous HCl (100 ml), saturated sodiumbicarbonate (100 ml), brine (100 ml), and dried (MgSO₄). Removal ofsolvent afforded 8.2 g (96%) of the title compound as yellow solids.

¹H-NMR (CDCl₃) δ: 9.48 (1H, br s), 7.60 (1H, d, J=8.6 Hz), 7.46-7.41(1H, m), 7.22-7.18 (1H, m), 7.11 (1H, dd, J=8.6, 1.8 Hz), 3.85 (3H, s),3.44 (3H, s).

Step 2. 6-Chloro-2-(3-chlorobenzoyl)indole

To a stirred solution of6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 1, 610 mg,2.56 mmol) and 3-bromochlorobenzene (1.47 g, 7.67 mmol) in THF (20 ml)at −78° C. was added dropwise n-butyllithium (1.54M in hexane, 4.90 ml,7.67 mmol). After stirring for 1 h, the mixture was quenched withsaturated ammonium chloride (20 ml), and extracted with ethyl acetate(50 ml×2). The combined organic extracts were washed with 2N aqueous HCl(50 ml), saturated sodium bicarbonate (50 ml), brine (50 ml), and dried(MgSO₄). After removal of solvent, the crude product was purified byflash column chromatography eluting with ethyl acetate/hexane (1:10) toafford 565 mg (76%) of the title compound as pale brown solids.

¹H-NMR (CDCl₃) δ: 9.31 (1H, br s), 7.94 (1H, t, J=1.9 Hz), 7.85 (1H, dt,J=1.9, 7.6 Hz), 7.65 (1H, d, J=8.4 Hz), 7.63-7.58 (1H, m), 7.52-7.45(2H, m), 7.18-7.12 (2H, m).

Step 3. Diethylα-Acetoxy-[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 6-chloro-2-(3-chlorobenzoyl)indole(step 2).

¹H-NMR (CDCl₃) δ: 8.88 (1H, br s), 7.87-7.74 (3H, m), 7.61-7.56 (1H, m),7.43 (1H, d, J=7.6 Hz), 7.41-7.38 (1H, m), 7.20-7.14 (1H, m), 4.30-4.14(4H, m), 1.74 (3H, s), 1.20 (6H, t, J=8.2 Hz).

Step 4. Diethyl[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate (step 3).

¹H-NMR (CDCl₃) δ: 8.87 (1H, br s), 7.79-7.74 (2H, m), 7.70-7.58 (2H, m),7.47 (1H, t, J=8.1 Hz), 7.39-7.37 (1H, m), 7.15 (1H, dd, J=1.8, 8.7 Hz),5.19 (1H, s), 4.27-4.10 (4H, m), 1.22 (6H, t, J=7.1 Hz).

Step 5. [6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate (step 4).

m.p.: 199-201° C. ¹H-NMR (DMSO-d₆) δ: 12.25 (1H, br s), 11.81 (1H, s),7.79-7.57 (5H, m), 7.48 (1H, d, J=1.8 Hz), 7.14 (1H, dd, J=1.8, 8.7 Hz),3.81 (2H, s).

Example 8 Methyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetateMethod A

Step 1. Methyl trans 4-Chloro-2-(phenylsulfonylamino)cinnamate

To a solution of methyl trans-2-amino-4-chlorocinnamate (R. W. Carlinget al., J. Med. Chem., 1993, 36, 3397., 30.7 g, 0.15 mol) and pyridine(36 ml, 0.45 mol) in dichloromethane (500 ml) was added benzenesulfonylchloride (20 ml, 0.16 mol). After stirring for 20 h, methanol (50 ml)was added and the mixture was concentrated. The residual solids weredissolved in dichloromethane (700 ml) and washed with 2N aqueous HCl(150 ml), brine (150 ml) and dried (MgSO₄). After removal of solvent,the residual solids were recrystallized from ethanol to give 40 g (76%)of the title compound as pale yellow solids.

¹H-NMR (CDCl₃) δ: 7.77-7.71 (2H, m), 7.59-7.52 (1H, m), 7.48-7.35 (5H,m), 7.20 (1H, dd, J=2.0, 8.4 Hz), 6.85 (1H, br s), 6.15 (1H, d, J=15.8Hz), 3.78 (3H, s).

Step 2.Methyl[6-chloro-2-(4-chlorobenzoyl)-1-(phenylsulfonyl)indolin-3-yl]acetate

A mixture of methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1, 1.1 g, 3.1 mmol), 4-chlorophenacylbromide (1.1 g, 4.6 mmol) andpotassium carbonate (2.1 g, 15.4 mmol) in acetone (10 ml) was stirred atroom temperature for 1.5 h. The mixture was filtered and the filtrateconcentrated. The residual solids were recrystallized from ethylacetate/hexane to afford 0.91 g (59%) of the title compound as paleyellow solids.

¹H-NMR (CDCl₃) δ: 7.97-7.94 (2H, m), 7.86-7.81 (2H, m), 7.65-7.58 (1H,m), 7.55-7.46 (5H, m), 7.02 (1H, dd, J=2.0, 8.2 Hz), 6.90 (1H, d, J=8.2Hz), 5.99 (1H, d, J=9.7 Hz), 4.00-3.87 (1H, m), 3.41 (3H, s), 2.63 (1H,dd, J=6.3, 17.6 Hz), 2.51 (1H, dd, J=6.3, 17.6 Hz).

Step 3. Methyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

To a stirred solution ofmethyl[6-chloro-2-(4-chlorobenzoyl)-1-(phenylsulfonyl)indolin-3-yl]acetate(step 2, 50 mg, 0.10 mmol) in THF was added1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 30 μl, 0.20 mmol). Afterstirring for 15 h, the mixture was quenched with water (30 ml), andextracted with ethyl acetate (50 ml). The extract was washed with 2Naqueous HCl (30 ml), saturated sodium bicarbonate (30 ml), brine (30ml), and dried (MgSO₄). Removal of solvent afforded 34 mg (93%) of thetitle compound as yellow solids.

MS (EI) m/z: 361 (M⁺). ¹H-NMR (CDCl₃) δ: 8.90 (1H, br s), 7.74 (2H, d,J=8.6 Hz), 7.56 (1H, d, J=8.6 Hz), 7.49 (2H, d, J=8.6 Hz), 7.36 (1H, d,J=1.6 Hz), 7.16 (1H, dd, J=1.6, 8.6 Hz), 3.81 (2H, s), 3.66 (3H, s).

Method B

A mixture of methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Method A, 0.70 g, 2.0 mmol), 4-chlorophenacyl bromide (0.51g, 2.2 mmol), and potassium carbonate (0.83 g, 6.0 mmol) in acetone (20ml) was stirred at room temperature. After stirring for 2h, cesiumcarbonate (2.0 g, 6.0 mmol) was added and the stirring was continued foran additional 4 h. The mixture was concentrated and the residue wasdiluted in water (100 ml). The aqueous mixture was extracted with ethylacetate (100 ml×2). The combined organic extracts were washed with 2Naqueous HCl (100 ml), saturated sodium bicarbonate (100 ml), brine (100ml), and dried (MgSO₄). After removal of solvent, the solids wererecrystalized from ethanol to afford 0.44 g (61%) of the title compound.

MS and NMR spectra were identical with those of the compound prepared instep 3.

Example 9 [6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic Acid MethodA

Step 1. 6-Chloro-2-(4-chlorobenzoyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 7 from6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1)and 4-bromochlorobenzene.

¹H-NMR (DMSO-d₆) δ: 12.14 (1H, br s), 7.97 (2H, d, J=8.41 Hz), 7.76 (1H,d, J=8.6 Hz), 7.66 (2H, d, J=8.4 Hz), 7.54-7.50 (1H, m), 7.20 (1H, s),7.14 (1H, dd, J=2.0, 8.6 Hz).

Step 2. Diethylα-Acetoxy-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 6-chloro-2-(4-chlorobenzoyl)indole(step 1).

¹H-NMR (CDCl₃) δ: 8.83 (1H, br s), 7.87-7.77 (3H, m), 7.48-7.36 (3H, m),7.17 (1H, dd, J=2.0, 8.9 Hz), 4.28-4.14 (4H, m), 1.73 (3H, s), 1.20(611, t, J=7.1 Hz).

Step 3. Diethyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate (step 2).

¹H-NMR (CDCl₃) δ: 8.91 (1H, br s), 7.75 (2H, d, J=8.6 Hz), 7.75-7.69(1H, m), 7.50 (2H, d, J=8.6 Hz), 7.29 (1H, d, J=1.8Hz), 7.13 (1H, dd,J=1.8, 8.7 Hz). 5.23 (1H, s), 4.28-4.07 (4H, m), 1.23 (6H, t, J=7.2 Hz).

Step 4. [6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate (step 3).

m.p.: 189-190° C. IR (KBr) ν: 3309, 1699, 1616, 1525, 1431, 1325, 1255,1226, 1091 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.78 (1H, s), 7.80-7.72 (3H, m),7.65 (2H, d, J=8.6 Hz), 7.47 (1H, d, J=1.8 Hz), 7.13 (1H, dd, J=1.8, 8.7Hz), 3.83 (2H, s).

Method B [6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic Acid

A mixture of methyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate(Example 8, 1.80 g) and 2N aqueous NaOH (7.5 ml) in MeOH-THF (10 ml-10ml) was stirred at 80° C. for 1 h. The mixture was cooled andconcentrated. The residue was dissolved in water (150 ml) and washedwith diethyl ether (50 ml). The aqueous layer was acidified with 2Naqueous HCl (10 ml), and extracted with ethyl acetate (100 ml×2). Thecombined organic extracts were washed with brine (50 ml), dried (MgSO₄),and concentrated. The residual solids were recrystalized from toluene toafford 1.58 g (91%) of the title compound.

IR and NMR spectra were identical with those of the compound prepared byMethod A.

Example 10 [6-Chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 6-Chloro-2-(3-fluorobenzoyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 7 from6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1)and 3-bromofluorobenzene.

¹H-NMR (CDCl₃) δ: 9.28 (1H, br s), 7.79-7.75 (1H, m), 7.68-7.63 (2H, m),7.56-7.48 (2H, m), 7.36-7.30 (1H, m), 7.17-7.14 (2H, m).

Step 2. Diethylα-Acetoxy-[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 6-chloro-2-(3-fluorobenzoyl)indole(step 1).

¹H-NMR (CDCl₃) δ: 9.15 (1H, br s), 8.83 (1H, d, J=8.72 Hz), 7.66-7.27(5H, m), 7.17 (1H, dd, J=2.00, 8.72 Hz), 4.254.13 (4H, m), 1.75 (3H, s),1.19 (6H, t, J=7.07 Hz).

Step 3. Diethyl[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]malonate (step 2).

¹H-NMR (CDCl₃) δ: 8.91 (1H, br s), 7.77-7.12 (7H, m), 5.21 (1H, s),4.25-4.11 (4H, m), 1.22 (6H, t, J=7.07 Hz).

Step 4. [6-Chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]malonate (step 3).

m.p.: 278-281° C. IR (KBr) ν: 3385, 1697, 1638, 1583, 1541, 1508, 1420,1400, 1315, 1261, 1236 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.79 (1H, s),7.76-7.48 (7H, m), 7.13 (1H, dd, J=1.97, 8.56 Hz), 3.80 (2H, s).

Example 11 [6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 6-Chloro-2-(4-fluorobenzoyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 7 from6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1)and 4-bromofluorobenzene.

¹H-NMR (CDCl₃) δ: 9.29 (1H, br s), 8.05-8.00 (2H, m), 7.64 (1H, d, 8.72Hz), 7.48-7.11 (5H, m).

Step 2. Diethylα-Acetoxy-[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 6-chloro-2-(4-fluorobenzoyl)indole(step 1).

¹H-NMR (CDCl₃) δ: 9.20 (1H, br s), 7.92-7.11 (7H, m), 4.25-4.14 (4H, m),1.73 (3H, s), 1.20 (6H, t, J=7.10 Hz).

Step 3. Diethyl[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]malonate (step 2).

¹H-NMR (CDCl₃) δ: 9.01 (1H, br s), 7.87-7.69 (2H, m), 7.71 (2H, d ,J=8.91 Hz), 7.27-7.10 (4H, m), 5.25 (1H, s), 4.26-4.11 (4H, m), 1.22(6H, t, J=7.07 Hz).

Step 4. [6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]malonate (step 3).

m.p.: 181-183° C. IR (KBr) ν: 3309, 1701, 1616, 1601, 1566, 1527, 1508,1419, 1323, 1257, 1229 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.75 (1H, s),7.87-7.82 (2H, m), 7.73 (1H, d, J=8.72), 7.47-7.36 (3H, m), 7.12 (1H,dd, J=1.84, 8.72 Hz), 3.78 (2H, s).

Example 12 [2-(3-Bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic Acid

Step 1. 2-(3-Bromobenzoyl)-6-chloroindole

The title compound was prepared according to the procedure described instep 2 of Example 7 from6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1)and 3-bromoiodobenzene.

¹H-NMR (CDCl₃) δ: 9.28 (1H, br s), 8.11-8.08 (1H, m), 7.93-7.87 (1H, m),7.79-7.73 (1H, m), 7.65 (1H, d, J=8.6 Hz), 7.50-7.38 (2H, m), 7.19-7.01(2H, m).

Step 2. Diethylα-Acetoxy-[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 2-(3-bromobenzoyl)-6-chloroindole(step 1).

¹H-NMR (CDCl₃) δ: 8.73 (1H, br s), 7.93 (1H, t, J=1.8 Hz), 7.85 (1H, d,J=8.6 Hz), 7.82-7.72 (2H, m), 7.42-7.32 (2H, m), 7.18 (1H, dd, J=2.0,8.6 Hz), 4.32-4.16 (4H, m), 1.75 (3H, s), 1.20 (6H, t, J=7.1 Hz).

Step 3. Diethyl[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate (step 2).

¹H-NMR (CDCl₃) δ: 8.88 (1H, br s), 7.92-7.90 (1H, m), 7.80-7.68 (3H, m),7.45-7.36 (2H, m), 7.15 (1H, dd, J=1.8, 8.7 Hz). 5.20 (1H, s), 4.304.10(4H, m), 1.23 (6H, t, J=7.2 Hz).

Step 4. [2-(3-Bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate (step 3).

m.p.: 215-218° C. IR (KBr) ν: 3369, 1710, 1604, 1558, 1533, 1423, 1319,1253, 1228 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.81 (11H, s), 7.92-7.83 (2H, m),7.78-7.70 (2H, m), 7.54 (1H, t, J=7.8 Hz), 7.48 (1H, d, J=2.0 Hz), 7.13(1H, dd, J=2.0, 8.7 Hz), 3.80 (2H, s).

Example 13 [2-(4-Bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic Acid

Step 1. 2-(4-Bromobenzoyl)-6-chloroindole

The title compound was prepared according to the procedure described instep 2 of Example 7 from6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1)and 4-bromoiodobenzene.

¹H-NMR (DMSO-d₆) δ: 12.28 (1H, br s), 7.88 (2H, d, J=8.7 Hz), 7.80 (2H,d, J=8.7 Hz), 7.76 (1H, d, J=8.7 Hz), 7.53-7.50 (1H, m), 7.22-7.19 (1H,m), 7.13 (1H, dd, J=2.0, 8.7 Hz).

Step 2. Diethylα-Acetoxy-[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 2-(4-bromobenzoyl)-6-chloroindole(step 1).

¹H-NMR (CDCl₃) δ: 8.72 (1H, br s), 7.84 (1H, d, J=8.7 Hz), 7.73 (2H, d,J=8.4 Hz), 7.62 (2H, d, J=8.4 Hz), 7.38 (1H, d, J=1.8 Hz), 7.18 (1H, dd,J=1.8, 8.7 Hz), 4.28-4.14 (4H, m), 1.73 (3H, s), 1.20 (6H, t, J=7.1 Hz).

Step 3. Diethyl[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate (step 2).

¹H-NMR (CDCl₃) δ: 8.86 (1H, br s), 7.75 (1H, d, J=8.4 Hz), 7.67 (4H, s),7.37-7.32 (1H, m), 7.18-7.12 (1H, m), 5.22 (1H, s), 4.26-4.10 (4H, m),1.23 (6H, t, J=7.1 Hz).

Step 4. [2-(4-Bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate (step 3).

m.p.: 199-201° C. IR (KBr) ν: 3300, 1699, 1618, 1587, 1525, 1433, 1406,1325, 1255, 1226 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.78 (1H, s), 7.80 (2H, d,J=8.4 Hz), 7.75 (1H, d, J=8.6 Hz), 7.69 (2H, d, J=8.4 Hz), 7.47 (1H, d,J=1.8 Hz), 7.13 (1H, dd, J=1.8, 8.6 Hz), 3.84 (2H, s).

Example 14 [6-Chloro-2-(3-trifluoromethylbenzoyl-1H-indol-3-yl)aceticAcid

Step 1. 6-Chloro-2-(3-trifluoromethylbenzoyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 7 from6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1)and 3-bromobenzotrifluoride.

¹H-NMR (DMSO-d₆) δ: 12.23 (1H, br s). 8.28-8.04 (3H, m), 7.89-7.75 (2H,m), 7.55-7.51 (1H, m), 7.22-7.12 (2H, m).

Step 2. Diethylα-Acetoxy-[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from6-chloro-2-(3-trifluoromethylbenzoyl)indole (step 1).

¹H-NMR (CDCl₃) δ: 8.82 (11H, br s), 8.25-7.80 (4H, m), 7.68-7.57 (1H,m), 7.43-7.41 (1H, m), 7.22-7.16 (1H, m), 4.36-4.20 (4H, m), 1.67 (3H,s), 1.20 (6H, t, J=7.1 Hz).

Step 3.Diethyl[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate(step 2).

¹H-NMR (CDCl₃) δ: 8.91 (11H, br s), 8.08-8.03 (1H, m), 8.02-7.87 (2H,m), 7.76 (1H, d, J=9.0 Hz), 7.73-7.64 (1H, m), 7.39-7.36 (1H, m), 7.15(1H, dd, J=1.8, 9.0 Hz). 5.15 (1H, s), 4.26-4.10 (4H, m), 1.22 (6H, t,J=7.2 Hz).

Step 4. [6-Chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate(step 3).

m.p.: 194-196° C. IR (KBr) ν: 3371, 1705, 1631, 1421, 1307, 1228, 1168,1122, 1072 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.86 (1H, s), 8.10-7.98 (3H, m),7.83 (1H, t, J=7.7 Hz), 7.75 (1H, d, J=8.6 Hz), 7.49 (1H, d, J=2.0 Hz),7.15 (11H, dd, J=2.0, 8.6 Hz), 3.80 (2H, s).

Example 15 [6-Chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]aceticAcid

Step 1. 6-Chloro-1-(phenylsulfonyl)-2-(4-trifluoromethylbenzoyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole(step 1 of Example 2, Method B) and 4-trifluoromethylbenzoyl chloride.

tlc: Rf=0.2 (ethyl acetate/hexane=1:4).

Step 2. 6-Chloro-2-(4-trifluoromethylbenzoyl)indole

The title compound was prepared according to the procedure described instep 3 of Example 2 (Method B) from6-chloro-1-phenylsulfonyl-2-(4-trifluoromethylbenzoyl) indole (step 1).

¹H-NMR (CDCl₃) δ: 9.53 (1H, br s), 7.94 (4H, dd, J=8.24, 69.1 Hz), 7.63(1H, d, J=8.56 Hz), 7.49-7.11 (3H, m).

Step 3. Diethylα-Acetoxy-[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from6-chloro-2-(4-trifluoromethylbenzoyl)indole (step 2).

¹H-NMR (CDCl₃) δ: 8.66 (1H, br s), 7.98 (2H, d, J=8.24 Hz), 7.87 (1H, d,J=8.91 Hz), 7.75 (2H, d, J=8.07 Hz), 7.39 (1H, d, J=1.81 Hz), 7.19 (1H,dd, J=1.81, 7.10 Hz), 4.36-4.16 (4H, m), 1.70 (3H, s), 1.34-1.22 (6H,m).

Step 4.Diethyl[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate(step 3).

¹H-NMR (CDCl₃) δ: 9.24 (1H, br s), 7.84 (4H, dd, J=7.91, 25.7 Hz),7.69-7.09 (3H, m), 5.24 (1H, s), 4.214.06 (4H, m), 1.21 (6H, t, J=7.07Hz).

Step 5. [6-Chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate(step 4).

¹H-NMR (DMSO-d₆) δ: 11.78 (1H, s), 7.94 (4H, s), 7.76 (1H, d, J=8.72Hz), 7.47 (1H, m), 7.14 (1H, d, J=1.81, 8.72), 3.81 (2H, s).

Example 16 [6-Chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 6-Chloro-2-(3,4-dichlorobenzoyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 7 from6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1)and 1-bromo-3,4-dichlorobenzene.

tlc: Rf=0.7 (ethyl acetate/hexane=1:3).

Step 2. Diethylα-Acetoxy-[6-chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from6-chloro-2-(3,4-dichlorobenzoyl)indole (step 1).

¹H-NMR (CDCl₃) δ: 8.80 (1H, br s), 7.90-7.79 (2H, m), 7.71 (1H, dd,J=2.0, 8.4 Hz), 7.57 (1H, d, J=8.4 Hz), 7.40-7.35 (1H, m), 7.18 (1H, dd,J=1.8, 8.8 Hz), 4.30-4.14 (4H, m), 1.77 (3H, s), 1.20 (6H, t, J=7.1 Hz).

Step 3. Diethyl[6-chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[6-chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]malonate (step2).

¹H-NMR (CDCl₃) δ: 8.95 (1H, br s), 7.88 (1H, d, J=1.6 Hz), 7.72 (1H, d,J=8.7 Hz), 7.68-7.58 (2H, m), 7.28 (1H, d, J=1.6 Hz), 7.14 (1H, dd,J=1.6, 8.7 Hz). 5.18 (1H, s), 4.28-4.10 (4H, m), 1.23 (6H, t, J=7.1 Hz).

Step 4. [6-Chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]malonate (step3).

m.p.: 206-209° C. IR (KBr) ν: 3435, 1708, 1620, 1583, 1525, 1423, 1384,1301, 1263, 1228 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.62 (1H, br s), 7.95-7.75(3H, m), 7.68 (1H, d, J=8.7 Hz), 7.42 (1H, d, J=2.0 Hz), 7.02 (1H, dd,J=2.0, 8.7 Hz), 3.50 (2H, s).

Example 17 (2-Benzoyl-4-chloro-1H-indol-3-yl)acetic Acid

Step 1. 4-Chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared according to the procedure described instep 1 of Example 7 employing 4-chloroindole-2-carboxylic acid (F. C.Uhle, J. Amer. Chem. Soc., 1949, 71, 761).

¹H-NMR (CDCl₃) δ: 9.56 (1H, br s), 7.36-7.29 (2H, m), 7.24-7.12 (2H, m),3.88 (3H, s), 3.45 (3H, s).

Step 2. 2-Benzoyl-4-chloroindole

To a solution of 4-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole(step 1, 3.4 g, 0.014 mol) in THF (60 ml) cooled to −78° C. was addeddropwise phenyllithium (1.8 M in cyclohexane/ether (7:3), 30 ml, 0.070mol). After stirring for 1 h, the mixture was poured into water (80 ml)and extracted with ethyl acetate (80 ml×2). After drying (MgSO₄) andremoval of solvent, the crude product was purified by flash columnchromatography eluting with ethyl acetate/hexane (1:10) to afford 3.6 g(100%) of the title compound as white solids.

¹H-NMR (CDCl₃) δ: 9.46 (1H, br s), 8.05-8.00 (2H, m), 7.73-7.51 (3H, m),7.40 (1H, dd, J=1.0, 8.3 Hz), 7.33-7.24 (2H, m), 7.18 (1H, d, J=7.6 Hz).

Step 3. Diethyl α-Acetoxy-(2-benzoyl-4-chloro-1H-indol-3-yl malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 2-benzoyl-4-chloroindole (step 2).

¹H-NMR (CDCl₃) δ: 9.49 (1H, br s), 7.98-7.92 (2H, m), 7.66-7.57 (11H,m), 7.53-7.44 (2H, m), 7.34 (1H, dd, J=2.0, 7.1 Hz), 7.21-7.15 (2H, m),4.30-3.90 (4H, m), 2.08 (3H, s), 1.15 (6H, t, J=7.3 Hz).

Step 4. Diethyl(2-benzoyl-4-chloro-1H-indol-3-yl)malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 from diethylα-acetoxy-(2-benzoyl-4-chloro-1H-indol-3-yl)malonate (step 3).

¹H-NMR (CDCl₃) δ: 8.88 (1H, br s), 7.83-7.77 (2H, m), 7.64-7.58 (1H, m),7.55-7.46 (2H, m), 7.25-7.05 (3H, m), 5.86 (1H, s), 4.25-4.08 (4H, m),1.23 (6H, t, J=7.3 Hz).

Step 5. (2-Benzoyl-4-chloro-1H-indol-3-yl)acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl(2-benzoyl-4-chloro-1H-indol-3-yl)malonate.

m.p.: 206-209° C. (recrystallized from ethyl acetate/hexane). IR (KBr)ν: 1700, 1575, 1245 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.20 (1H, br s), 11.98(1H, s), 7.85-7.67 (3H, m), 7.63-7.55 (2H, m), 7.45 (1H, d, J=8.2 Hz),7.25 (1H, t, J=8.2 Hz), 7.12 (1H, d, J=7.6 Hz), 4.02 (2H, s).

Example 18 [5-Chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 5-Chloro-2-[(N-method-N-methylamino)carbonyl]indole

The title compound was prepared according to the procedure described instep 1 of Example 7 from 5-chloroindole-2-carboxylic acid.

¹H-NMR (CDCl₃) δ: 9.68 (1H, br s), 7.68-7.65 (1H, m), 7.37 (1H, d, J=8.7Hz), 7.23 (1H, d, J=1.6 Hz), 7.18-7.15 (1H, m), 3.85 (3H, s), 2.05 (3H,s).

Step 2. 5-Chloro-2-(3-methylbenzoyl]indole

The title compound was prepared according to the procedure described instep 2 of Example 17 from5-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 1) and3-methylphenyllithium.

m.p.: 197.5-198° C. (recrystallized from ethyl acetate/hexane). IR (KBr)ν: 3310, 1626, 1603, 1583, 1516, 1406, 1377, 1337, 1269, 1178, 1134cm⁻¹. ¹H-NMR (CDCl₃) δ: 9.39 (1H, br s), 7.28-7.76 (2H, m), 7.71-7.68(1H, m), 7.46-7.38 (3H, m), 7.32 (1H, dd, J=8.7, 2.0 Hz), 7.08 (1H, dd,J=2.0, 0.8 Hz), 2.47 (3H, s).

Step 3. Diethylα-Acetoxy-[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 5-chloro-2-(3-methylbenzoyl)indole(step 2).

m.p.: 173-174° C. (recrystallized from ethyl acetate/hexane). ¹H-NMR(CDCl₃) δ: 8.64 (1H, br s), 7.91 (1H, br s), 7.69-7.61 (2H, m),7.46-7.22 (4H, m), 4.304.16 (4H, m), 2.39 (3H, s), 1.72 (3H, s), 1.23(3H, t, J=7.2 Hz).

Step 4. Diethyl[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl] malonate (step3).

m.p.: 143-144° C. (recrystallized from ethyl acetate/hexane). ¹H-NMR(CDCl₃) δ: 8.88 (1H, br s), 7.84-7.80 (1H, m), 7.62-7.55 (2H, m),7.48-7.36 (2H, m), 7.32-7.28 (2H, m), 5.27 (1H, s), 4.30-4.10 (4H, m),2.42 (3H, s), 1.24 (3H, t, J=7.1 Hz).

Step 5. [5-Chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate.

m.p.: 241-242° C. (recrystallized from ethyl acetate/hexane). IR (KBr)ν: 3321, 1703, 1618, 1535, 1431, 1335, 1232, 1016, 808, 758 cm⁻¹. ¹H-NMR(DMSO-d₆) δ: 11.7 (1H, br s), 7.62 (1H, d, J=1.8 Hz), 7.45-7.30 (6H, m),7.19 (11H, dd, J=8.6, 1.8 Hz), 3.63 (2H, s), 2.27 (3H, s).

Example 19 [5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 5-Chloro-2-(4-chlorobenzoyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 7 from5-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 18,step 1) and 4-bromochlorobenzene.

¹H-NMR (CDCl₃) δ: 9.32 (1H, br s), 7.94 (2H, d, J=8.4 Hz), 7.70 (1H, s),7.53 (2H, d, J=8,4 Hz), 7.42 (1H, d, J=8.9 Hz), 7.34 (1H, dd, J=2.0, 8.9Hz), 7.07 (1H, s).

Step 2. Diethylα-Acetoxy-[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 5-chloro-2-(4-chlorobenzoyl)indole(step 1).

¹H-NMR (CDCl₃) δ: 9.11 (1H, br s), 7.87 (1H, s), 7.76 (2H, d, J=8.6 Hz),7.41 (2H, d, J=8.6 Hz), 7.27 (1H, d, J=8.7 Hz), 7.22 (1H, dd, J=1.8, 8.7Hz), 4.25-4.14 (4H, m), 1.72 (3H, s), 1.24-1.19 (6H, m).

Step 3. Diethyl[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate (step 2).

¹H-NMR (CDCl₃) δ: 9.13 (1H, br s), 7.73 (2H, d, J=8.4 Hz), 7.68 (1H, d,J=2.0 Hz), 7.48 (2H, d, J=8.4 Hz), 7.11 (1H, dd, J=2.0, 8.9 Hz), 7.02(1H, d, J=8.9 Hz), 5.28 (1H, s), 4.24-4.03 (4H, m), 1.27-1.21 (6H, m).

Step 4. [5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate (step 3).

m.p.: 220-224° C. (recrystallized from ethyl acetate/hexane). IR (KBr)ν: 3321, 1618, 1535, 1379, 1339, 1263, 1130, 1090, 1057, 1007 cm⁻¹.¹H-NMR (DMSO-d₆) δ: 11.83 (1H, s), 7.80-7.75 (3H, m), 7.67-7.62 (2H, m),7.48 (1H, d, J=8.7 Hz), 7.31 (1H, dd, J=2.0, 8.7 Hz), 3.84 (2H, s).

Example 20 [5-Chloro-2-(3-Chlorobenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 5-Chloro-2-(3-chlorobenzoyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 7 from5-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 18,step 1) and 3-bromochlorobenzene.

¹H-NMR (CDCl₃) δ: 9.28 (1H, br s), 7.95 (1H, t, J=1.7 Hz), 7.88-7.84(1H, m), 7.71 (1H, d, J=2.0 Hz), 7.63-7.59 (1H, m), 7.49 (1H, t, J=7.7Hz), 7.42 (1H, d, J=8.7 Hz), 7.34 (1H, dd, J=2.0, 8.7 Hz), 7.10-7.09(1H, m).

Step 2. Diethylα-Acetoxy-[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 5-chloro-2-(3-chlorobenzoyl)indole(step 1).

¹H-NMR (CDCl₃) δ: 8.94 (1H, br s), 7.91 (1H, d, J=1.8 Hz), 7.79-7.76(1H, m), 7.74 (1H, d, J=7.7 Hz), 7.60-7.56 (1H, m), 7.42 (1H, t, J=7.7Hz), 7.33 (1H, d, J=8.7 Hz), 7.27 (1H, dd, J=1.8, 8.7 Hz), 4.37-4.19(4H, m), 1.75 (3H, s), 1.26-1.20 (6H, m).

Step 3. Diethyl[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate (step 2).

¹H-NMR (CDCl₃) δ: 9.04 (1H, br.s), 7.77-7.75 (2H, m), 7.68-7.58 (2H, m),7.46 (1H, t, J=7.7 Hz), 7.24-7.20 (2H, m), 5.23 (1H, s), 4.27-4.14 (4H,m), 1.27-1.22 (6H, m).

Step 4. [5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate (step 3).

m.p.: 243-247° C. (recrystallized from ethyl acetate/hexane). IR (KBr)ν: 3329,1707, 1618, 1535, 1431, 1406, 1375, 1333, 1279, 1232, 1053 cm⁻¹.¹H-NMR (DMSO-d₆) δ: 11.87 (1H, s), 7.81-7.68 (4H, m), 7.64-7.58 (1H, m),7.49 (1H, d, J=8.9 Hz), 7.32 (1H, dd, J=2.0, 8.9 Hz), 3.82 (2H, s).

Example 21 [2-(4-Chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic Acid

Step 1. 5-Fluoro-2-[(N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared according to the procedure described instep 1 of Example 7 from 5-fluoroindole-2-carboxylic acid.

¹H-NMR (CDCl₃) δ: 10.15 (1H, br s), 7.41-7.36 (1H, m), 7.32 (1H, dd,J=2.5, 9.1 Hz), 7.20-7.19 (1H, m), 7.09-7.01 (1H, m), 3.84 (3H, s), 3.47(3H, s).

Step 2. 2-(4-Chlorobenzoyl)-5-fluoro-indole

The title compound was prepared according to the procedure described instep 2 of Example 7 from5-fluoro-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 1) and4-bromochlorobenzene.

¹H-NMR (CDCl₃) δ: 9.27 (1H, br s), 7.94 (2H, d, J=8.4 Hz), 7.52 (2H, d,J=8.4 Hz), 7.45-7.40 (1H, m), 7.37-7.33 (1H, m), 7.21-7.12 (1H, m),7.10-7.09 (1H, m).

Step 3. Diethylα-Acetoxy-[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 2-(4-chlorobenzoyl)-5-fluoroindole(step 2).

¹H-NMR (CDCl₃) δ: 9.01 (1H, br s), 7.80-7.77 (2H, m), 7.58-7.54 (1H ,m),7.45-7.41 (2H, m), 7.36-7.27 (1H, m), 7.12-7.01 (1H, m), 4.29-4.15 (4H,m), 1.74 (3H, s), 1.28-1.17 (6H, m).

Step 4. Diethyl[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate (step 3).

¹H-NMR (CDCl₃) δ: 8.98 (1H, br s), 7.77-7.72 (2H, m), 7.51-7.46 (2H, m),7.40 (1H, dd, J=2.5, 9.7 Hz), 7.18-7.13 (1H, m), 7.04-6.96 (1H, m), 5.28(1H, s), 4.26-4.07 (4H, m), 1.30-1.18 (6H, m).

Step 5. [2-(4-Chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate (step 4).

m.p.: 233-238° C. (recrystallized from ethyl acetate/hexane). IR (KBr)ν: 3317, 1707, 1624, 1609, 1587, 1526, 1458, 1408, 1344, 1263, 1242cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.73 (1H, s), 7.77 (2H, d, J=8.6 Hz), 7.65(2H, d, J=8.6 Hz), 7.52-7.44 (2H, m), 7.22-7.15 (1H, m), 3.84 (2H, s).

Example 22 [2-(3-Chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic Acid

Step 1. 2-(3-Chlorobenzoyl)-5-fluoroindole

The title compound was prepared according to the procedure described instep 2 of Example 7 from5-fluoro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 21,step 1) and 3-bromochlorobenzene.

¹H-NMR (CDCl₃) δ: 9.29 (1H, m), 7.96-7.94 (1H, m), 7.88-7.84 (1H, m),7.63-7,59 (1H, m), 7.48 (1H, t, J=8.0 Hz), 7.45-7.40 (1H, m), 7.36 (1H,dd, J=2.6, 8.6 Hz), 7.20-7.11 (2H, m).

Step 2. Diethylα-Acetoxy-[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 2-(3-chlorobenzoyl)-5-fluoroindole(step 1).

¹H-NMR (CDCl₃) δ: 8.73 (1H, br s), 7.79-7.74 (2H, m), 7.61-7.56 (2H, m),7.43 (1H, t, J=7.6 Hz), 7.37-7.32 (1H, m), 7.13-7.06 (1H, m), 4.34-4.20(4H, m), 1.76 (3H, s), 1.33-1.20 (6H, m).

Step 3. Diethyl[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylo:-acetoxy-[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate (step2).

¹H-NMR (CDCl₃) δ: 9.05 (1H, br s), 7.76-7.75 (1H, m), 7.68-7.64 (1H, m),7.61-7.56 (1H, m), 7.48-7.40 (2H, m), 7.24-7.19 (1H, m), 7.08-7.00 (1H,m), 5.25 (1H, s), 4.28-4.07 (4H, m), 1.33-1.21 (6H, m).

Step 4. [2-(3-Chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate (step 3).

m.p.: 208-212° C. (recrystallized from ethyl acetate/hexane). IR (KBr)ν: 3337, 1709, 1618, 1560, 1529, 1477, 1458, 1427, 1408, 1335, 1304cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.78 (1H, s), 7.77-7.58 (4H, m), 7.52-7.46(2H, m), 7.24-7.16 (1H, m), 3.82 (2H, s).

Example 23 [5-Methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 5-Methoxy-2-[(N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared according to the procedure described instep 1 of Example 7 from 5-methoxyindole-2-carboxylic acid.

¹H-NMR (CDCl₃) δ: 9.29-9.13 (1H, br), 7.33 (1H, d, J=8.9 Hz), 7.19-7.14(1H, m), 7.10 (1H, d, J=2.3 Hz), 6.98 (1H, dd, J=8.9, 2.3 Hz), 3.86 (3H,s), 3.84 (3H, s), 3.42 (3H, s).

Step 2. 5-Methoxy-2-(3-methylbenzoyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 17 from5-methoxy-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 1) and3-methylphenyllithium.

¹H-NMR (CDCl₃) δ: 9.65-9.45 (1H, br), 7.84-7.75 (2H, m), 7.46-7.35 (3H,m), 7.12-7.01 (3H, m), 3.85 (3H, s), 2.46 (3H, s).

Step 3. Diethylα-Acetoxy-[5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 5-methoxy-2-(3-methylbenzoyl)indole(step 2).

tlc: Rf=0.45 (ethyl acetate/hexane=1:3).

Step 4. Diethyl[5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate (step3).

¹H-NMR (CDCl₃) δ: 9.52-9.13 (0.5H, m), 8.81-8.71 (0.5H, m), 7.80-7.72(1H, m), 7.63-7.55 (1H, m), 7.47-7.00 (5H, m), 5.41 (0.5H, s), 5.37(0.5H, s), 4.27-4.15 (4H, m), 3.89 (1.5H, s), 3.84 (1.5H, s), 2.45(1.5H, s), 2.43 (1.5H, s), 1.29-1.19 (6H, m).

Step 5. [5-Methoxy-2-(3-methylbenzoyl-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate (step 4).

m.p.: 230.4-232.0° C. (decomposed) (recyrstallized from ethyl acetate).IR (KBr) ν: 3310, 1705, 1614, 1583 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.47 (1H,br s), 7.60-7.34 (5H, m), 7.16-7.09 (1H, m), 6.98 (1H, dd, J=9.0, 2.4Hz), 3.78 (5H, s), 2.40 (3H, s). ¹³C-NMR (DMSO-d₆) δ: 188.1, 172.1,153.8, 138.9, 137.9, 132.7, 132.3, 132.0, 129.2, 128.5, 128.0, 125.8,117.0, 115.6, 113.6, 100.7, 55.3, 30.6, 20.8.

Example 24 (2-Benzoyl-7-chloro-1H-indol-3-yl)acetic Acid

Step 1. 7-Chloro-2-[N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared according to the procedure described instep 1 of Example 7 from 7-chloroindole-2-carboxylic acid (H. N. Rydonand J. C. Tweddle, J. Chem. Soc., 1955, 3499).

¹H-NMR (CDCl₃) δ: 9.40 (1H, br s), 7.59 (1H, d, J=8.1 Hz), 7.32-7.25(2H, m), 7.08 (1H, t, J=8.1 Hz), 3.85 (3H, s), 3.43 (3H, s).

Step 2. 2-Benzoyl-7-chloroindole

The title compound was prepared according to the procedure described instep 2 of Example 17 from7-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 1) andphenyllithium.

¹H-NMR (CDCl₃) δ: 9.40 (1H, br s), 8.01-7.96 (2H, m), 7.70-7.50 (4H, m),7.38 (1H, d, J=7.6 Hz), 7.18 (1H, d, J=2.0 Hz), 7.11 (1H, t, J=7.6 Hz).

Step 3. Diethyl α-Acetoxy-(2-benzoyl-7-chloro-1H-indol-3-yl)malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 2-benzoyl-7-chloroindole (step 2).

¹H-NMR (CDCl₃) δ: 8.76 (1H, br s), 7.92-7.81 (3H, m), 7.68-7.60 (1H, m),7.53-7.45 (2H, m), 7.33 (1H, d, J=7.6 Hz), 7.15 (1H, t, J=8.2 Hz),4.60-4.20 (4H, m), 1.71 (3H, s), 1.98 (6H, t, J=7.1 Hz).

Step 4. Diethyl(2-benzoyl-7-chloro-1H-indol-3-yl)malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-(2-benzoyl-7-chloro-1H-indol-3-yl)malonate (step 3).

¹H-NMR (CDCl₃) δ: 8.94 (1H, br s), 7.86-7.80 (2H, m), 7.75 (1H, d, J=8.1Hz), 7.70-7.62 (1H, m), 7.55-7.50 (2H, m), 7.36 (1H, d, J=7.6 Hz), 7.13(1H, t, J=7.6 Hz), 5.29 (1H, s), 4.25-4.11 (4H, m), 1.22 (6H, t, J=7.3Hz).

Step 5. (2-Benzoyl-7-chloro-1H-indol-3-yl)acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl(2-benzoyl-7-chloro-1H-indol-3-yl)malonate (step 4).

m.p.: 190-193° C. (recrystallized from ethyl acetate/hexane) IR (KBr) ν:1691, 1627, 1598, 1323, 1260 1199, 1010 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.90(1H, br s), 7.82 (2H, m), 7.74-7.65 (2H, m), 7.62-7.38 (2H, m), 7.40(1H, d, J=7.6 Hz), 7.13 (1H, t, J=7.6 Hz), 3.75 (2H, s).

Example 25 (2-Benzoyl-4,5-dichloro-1 H-indol-3-yl)acetic Acid

Step 1. 4,5-Dichloroindolyl-2-carboxylic Acid

To a suspension of ethyl 4,5-dichloroindole-2-carboxylate (Ishii et al.,Chem. Pharm. Bull., 1974, 22, 1981., 1.8 g, 7.0 mmol) in ethanol (40 ml)was added 2N aqueous NaOH (10 ml) and the mixture was heated at refluxtemperature for 2 h. The mixture was cooled to room temperature andconcentrated. The residual solid was acidified with 2N aqueous HCl (30ml) and extracted with diethyl ether (80 ml×2). The organic extractswere dried (MgSO₄) and concentrated to give 1.5 g (94%) of the titlecompound as yellow solids.

¹H-NMR (DMSO-d₆) δ: 12.34 (1H, br s), 7.47-7.39 (2H, m), 7.08 (1H, d,J=1.8 Hz).

Step 2. 4,5-Dichloro-2-[N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared according to the procedure described instep 1 of Example 7 from 4,5-dichloroindole-2-carboxylic acid (step 1).

¹H-NMR (CDCl₃) δ: 9.62 (1H, br s), 7.40-7.05 (3H, m), 3.88 (3H, s), 3.45(3H, s).

Step 3. 2-Benzoyl-4,5-dichloroindole

The titled compound was prepared according to the procedure described instep 2 of Example 17 from4,5-dichloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 2) andphenyllithium.

m.p.: 206-210° C. (recrysallized from ethyl acetate/hexane). ¹H-NMR(CDCl₃) δ: 9.58 (1H, br s), 8.05-7.98 (2H, m), 7.71-7.53 (3H, m), 7.42(1H, d, J=8.9 Hz), 7.35 (1H, d, J=8.9 Hz), 7.22 (1H, s).

Step 4. Diethyl α-Acetoxy-(2-benzoyl-4,5-dichloro-1H-indol-3-yl)malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 2-benzoyl-4,5-dichloroindole (step3).

¹H-NMR (CDCl₃) δ: 8.85 (1H, br s), 7.91-7.86 (2H, m), 7.66-7.58 (1H, m),7.52-7.44 (2H, m), 7.36 (1H, d, J=8.7 Hz), 7.21 (1H, d, J=8.7 Hz),4.20-3.98 (4H, m), 2.07 (3H, s), 1.15 (6H, t, J=7.3 Hz).

Step 5. Diethyl(2-benzoyl-4,5-dichloro-1H-indol-3-yl)malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-(2-benzoyl-4,5-dichloro-1H-indol-3-yl)malonate (step 4).

¹H-NMR (CDCl₃) δ: 9.24 (1H, br s), 7.82-7.76 (2H, m), 7.65-7.58 (1H, m),7.55-7.44 (2H, m), 7.20 (1H, d, J=8.7 Hz), 7.03 (1H, d, J=8.7 Hz), 5.89(1H, s), 4.16-4.02 (4H, m), 1.20 (6H, t, J=7.3 Hz).

Step 6. (2-Benzoyl-4,5-dichloro-1H-indol-3-yl)acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl(2-benzoyl-4,5-dichloro-1H-indol-3-yl)malonate (step 5).

m.p.: 249-252° C. (recrystallized from ethyl acetate/hexane). IR (KBr)ν: 1701, 1625, 1523, 1450, 1330, 1257, 1012 cm⁻¹. ¹H-NMR (CDCl₃) δ: 9.92(1H, br s), 7.85-7.81 (2H, m), 7.66-7.42 (3H, m), 7.36 (1H, d, J=8.8Hz), 7.29 (1H, d, J=8.8 Hz), 4.09 (2H, s).

Example 26 (2-Benzoyl-4,6-dichloro-1H-indol-3-yl)acetic Acid

Step 1. 4,6-Dichloro-2-(N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared according to the procedure described instep 1 of Example 7 from 4,6-dichloroindole-2-carboxylic acid (Salituro,Francesco G. et al., J. Med. Chem., 1990, 33, 2944).

¹H-NMR (DMSO-d₆) δ: 12.09 (1H, br s), 7.48 (1H, dd, J=1.0, 1.6 Hz), 7.25(1H, d, J=1.6 Hz), 7.11 (1H, s), 3.82 (3H, s), 3.63 (3H, s).

Step 2. 2-Benzoyl-4,6-dichloroindole

The titled compound was prepared according to the procedure described instep 2 of Example 17 from4,6-dichloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 1) andphenyllithium.

m.p.: 214-218° C. ¹H-NMR (CDCl₃) δ: 9.45 (1H, br s), 8.02-7.95 (2H, m),7.70-7.52 (3H, m), 7.40 (1H, d, J=1.6 Hz), 7.25 (1H, s), 7.20 (1H, d,J=1.6 Hz).

Step 3. Diethyl α-Acetoxy-(2-benzoyl-4,6-dichloro-1H-indol-3-yl)malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 2-benzoyl-4,6-dichloroindole (step2).

¹H-NMR (CDCl₃) δ: 8.92 (1H, br s), 7.95-7.86 (2H, m), 7.68-7.43 (3H, m),7.29 (1H, d, J=1.8 Hz), 7.23 (1H, d, J=1.8 Hz), 4.60-4.00 (4H, m), 2.04(3H, s), 1.30-1.10 (6H, m).

Step 4. Diethyl(2-benzoyl-4,6-dichloro-1H-indol-3-yl)malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-(2-benzoyl-4,6-dichloro-1H-indol-3-yl)malonate (step 3).

m.p.: 170-172° C. ¹H-NMR (CDCl₃) δ: 9.15 (1H, br s), 7.84-7.75 (2H, m),7.66-7.45 (3H, m), 7.26 (1H, s), 7.12 (1H, s), 5.79 (1H, s), 4.20-4.00(4H, m), 1.20 (6H, t, J=7.3 Hz).

Step 5. (2-Benzoyl-4,6-dichloro-1H-indol-3-yl)acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[2-benzoyl-4,5-dichloro-1H-indol-3-yl]malonate (step 4).

m.p.: 239-243° C. (recrystallized from ethyl acetate/hexane). IR (KBr)ν: 1725, 1555, 1525, 1330, 1287, 1250, 1005 cm⁻¹. ¹H-NMR (DMSO-d₆) δ:12.40 (1H, br s), 12.12 (1H, br s), 7.80-7.67 (3H, m), 7.64-7.54 (2H,m), 7.48 (1H, d, J=1.8 Hz), 7.23 (1H, d, J=1.8 Hz), 3.99 (2H, s).

Example 27 (2-Benzoyl-5,6-dichloro-1H-indol-3-yl)acetic Acid

Step 1. 5,6-Dichloroindole-2-carboxylic Acid

The title compound was prepared according to the procedure described instep 1 of Example 25 from ethyl 5,6-dichloroindole-2-carboxylate (Ishiiet al., Chem. Pharm. Bull., 1974, 22, 1981).

¹H-NMR (DMSO-d₆) δ: 12.06 (1H, br s), 7.95 (1H, s), 7.62 (1H, s), 7.09(1H, s).

Step 2. 5,6-Dichloro-2-[N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared according to the procedure described instep 1 of Example 7 from 5,6-dichloroindole-2-carboxylic acid (step 1).

¹H-NMR (CDCl₃) δ: 11.86 (1H, br s), 7.96 (1H, s), 7.66 (1H, s), 7.16(1H, s), 3.80 (3H, s), 3.34 (3H, s).

Step 3. 2-Benzoyl-5,6-dichloroindole

The titled compound was prepared according to the procedure described instep 2 of Example 17 from5,6-dichloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 2) andphenyllithium.

m.p.: 206-210° C. (recyrstallized from ethyl acetate/hexane). ¹H-NMR(CDCl₃) δ: 9.35 (1H, br s), 8.00-7.93 (2H, m), 7.81 (1H, s), 7.69-7.51(3H, m), 7.26 (1H, s), 7.08 (1H, s).

Step 4. Diethyl α-Acetoxy-(2-benzoyl-5,6-dichloro-1H-indol-3-yl)malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 2-benzoyl-5,6-dichloroindole (step3).

¹H-NMR (CDCl₃) δ: 8.76 (1H, br s), 8.05 (1H, s), 7.90-7.82 (2H, m),7.67-7.59 (1H, m), 7.54-7.44 (3H, m), 4.30-4.10 (4H, m), 1.69 (3H, s),1.35-1.20 (6H, m).

Step 5. Diethyl(2-benzoyl-5,6-dichloro-1H-indol-3-yl)malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-(2-benzoyl-5,6-dichloro-1H-indol-3-yl)malonate (step 4).

¹H-NMR (CDCl₃) δ: 8.90 (1H, br s), 7.95 (1H, s), 7.82-7.76 (2H, m),7.70-7.61 (1H, m), 7.58-7.46 (3H, m), 5.26 (1H, s), 4.30-4.05 (4H, m),1.24 (6H, t, J=7.1 Hz).

Step 6. (2-Benzoyl-5,6-dichloro-1H-indol-3-yl)acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl(2-benzoyl-4,5-dichloro-1H-indol-3-yl)malonate (step 5).

m.p.: 208-210° C. (recrystallized from ethyl acetate/hexane). ¹H-NMR(DMSO-d₆) δ: 11.91 (1H, br s), 8.04 (1H, s), 7.77-7.50 (6H, m), 3.81(2H, s).

Example 28 dl-2-(2-Benzoyl-6-chloro-1H-indol-3-yl)propanic Acid

Step 1. Diethyl α-Methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 2-benzoyl-6-chloroindole (step 3 ofExample 2, Method B) and diethyl methylmalonate.

m.p.: 193-196° C. ¹H-NMR (CDCl₃) δ: 8.42 (1H, br s), 7.87 (2H, m),7.66-7.48 (3H, m), 7.42 (1H, d, J=8.8 Hz), 7.35 (1H, d, J=1.8 Hz), 7.11(1H, dd, J=1.8, 8.8 Hz), 4.30-4.02 (4H, m), 1.98 (3H, s), 1.15 (6H, t,J=7.1 Hz).

Step 2. dl-2-(2-Benzoyl-6-chloro-1H-indol-3-yl)propanoic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) from diethylα-methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)malonate (step 1).

m.p.: 204-208° C. (recrystallized from dichloromethane/hexane). IR(KBr)ν: 1720, 1620, 1475, 1260, 1230 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.29(1H, br s), 11.72 (1H, br s), 7.82-7.76 (2H, m), 7.75-7.68 (2H, m),7.65-7.57 (2H, m), 7.48 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=1.8, 8.4 Hz),4.15 (1H, q, J=7.1 Hz), 1.44 (3H, d, J=7.1 Hz).

Example 29 and Example 30 Less Polar Antipode,2-(2-Benzoyl-6-chloro-1H-indol-3-yl)propanic Acid (Example 29) and MorePolar Antipode, 2-(2-Benzoyl-6-chloro-1H-indol-3-yl)propanic Acid(Example 30)

Chiral separation of dl-2-(2-Benzoyl-6-chloro-1H-indol-3-yl)propanoicacid (Example 28) was performed by DAICEL CHIRALCEL OJ (4.6×250 mm,eluent: hexane/isopropanol/trifluoroacetic acid=85:15:0.1, flow rate:1.0 ml/min) to afford; less polar compound (retention time: 17 mm.) andmore polar compound (retention time: 27 min.).

Example 31[6-Chloro-2-(4-methylpyridine-2-Carbonyl)-1H-indol-3-yl]acetic Acid

Step 1. Methyl trans-4-Chloro-2-(ethoxycarbonylamino)cinnamate

To a stirred solution of methyl trans-2-amino-4-chlorocinnamate (R. W.Carling et al., J. Med. Chem. 1993, 36, 3397., 32.6 g, 0.15 mol),pyridine (14.9 ml, 0.17 mol) and 4-dimethylaminopridine (0.5 g) indichloromethane (500 ml) was added dropwise ethyl chloroformate (16.2ml, 0.17 mol) at room temperature. After stirring for 2h, the mixturewas concentrated. The residue was diluted in ethyl acetate (1000 ml) andwashed with 10% aqueous citric acid (500 ml). The organic layer wassuccessively washed with water (500 ml), saturated sodium bicarbonate(500 ml), water (500 ml), brine (500 ml). After drying (MgSO₄) andremoval of solvent, the residual solids were recrystallized from ethylacetate/hexane to give 39.13 g (92%) of the title compound.

¹H-NMR (CDCl₃) δ: 7.95 (1H, br s), 7.76 (1H, d, J=15.8 Hz), 7.42 (1H, d,J=8.6 Hz), 7.22 (1H, dd, J=2.1, 8.5 Hz), 6.69 (1H, br), 6.37 (1H, d,J=15.7 Hz), 4.26 (2H, q, J=7.3 Hz), 3.82 (3H, s), 1.34 (3H, t, J=7.25Hz).

Step 2.Methyl[6-chloro-1-ethoxycarbonyl-2-(4-methylpyridine-2-carbonyl)indolin-3-yl]acetate

A mixture of methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate(step 1, 1.5 g, 5.3 mmol), 2-bromoacetyl-4-methylpyridine hydrobromide*,potassium carbonate (7.3 g, 53 mmol) and acetonitrile (50 ml) was heatedat reflux temperature for 17 h. The mixture was then cooled andconcentrated. The residue was diluted in ethyl acetate (200 ml) andwashed with water (200 ml) and brine (200 ml). After drying (MgSO₄) andremoval of solvent, the crude product was purified by flash columnchromatography eluting with ethyl acetate/hexane (1:5) to afford 433 mg(20%) of the title compound.

* 2-bromoacetyl-4-methylpyridine hydrobromide was prepared as follows;

MS (EI) m/z: 416 (M+).

To a stirred solution of 2-acetyl-4-methylpyridine (F. H. Case et al, J.Am. Chem. Soc., 1956, 78, 5842., 7.8 g, 57.7 mmol) in 25% HBr—AcOH (40ml) was added dropwise a solution of bromine (10.1 g, 63.5 mmol) in AcOH(10 ml) with ice-cooling. After stirring for 1 h, diethyl ether (100 m)was added and the precipitates were collected by filtration to give 10.8g (63%) of the title compound.

¹H-NMR (DMSO-d₆) δ: 8.71 (1H, d, J=5.1 Hz), 8.14 (1H, s), 7.75 (1H, d,J=5.1 Hz), 5.07 (2H, s), 2.52 (3H, s).

Step 3. [6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]aceticAcid

A stirred solution ofmethyl[6-chloro-1-ethoxycarbonyl-2-(4-methylpyridine-2-carbonyl)indolin-3-yl]acetate(step 2, 930 mg, 2.2 mmol) in ethanol (20 ml) and 2N aqueous NaOH (10ml) was heated at reflux temperature for 72 h. After cooling to roomtemperature, the resulting mixture was neutralized with 2N aqueous HCl(10 ml) and concentrated. The residue was diluted indichloromethane/mehanol (10:1, 300 ml) and dried (MgSO₄). After removalof solvent, the crude product was purified by flash columnchromatography eluting with dichloromethane/methanol (20:1) and thenwashed with i-PrOH (ca.20 ml) to give 120 mg (17%) of the title compoundas a yellow powder.

m.p.: 223° C. (decomposed). IR (KBr) ν: 1707, 1647, 1595, 1533, 1487,1429, 1276, 1289, 1196 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.30 (1H, s), 8.70(1H, d, J=4.9 Hz), 7.96 (1H, br s), 7.85-7.70 (2H, m), 7.65-7.55 (1H,m), 7.17-7.07 (1H, m), 4.08 (2H, s), 2.47 (3H, s).

Example 32[6-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

Step 1.Methyl[6-chloro-1-ethoxycarbonyl-2-(5-methylpyridine-2-carbonyl)indolin-3-yl]acetate

Two diastreomers of the title compound were prepared according theprocedure described in step 2 of Example 31 from methyltrans-4-chloro-2-(ethoxycarbonylamino)cinnamate (Example 31, step 1) and2-bromoacetyl-5-methylpyridine.*

* 2-Bromoacetyl-5-methylpyridine was prepared as follows;

Less polar product; tlc: Rf=0.30 (ethyl acetate/hexane=1/2), MS (EI)m/z: 416 (M⁺).

More polar product; tlc: Rf=0.25 (ethyl acetate/hexane=1/2), MS (EI)m/z: 416 (M⁺).

A mixture of 2-bromo-5-methylpyridine (5.00 g, 29.06 mmol),tributyl(1-ethoxyvinyl)tin (10.49 g, 29.07 mmol), andtetrakis(triphenylphosphine)palladium (3.36 g, 2.91 mmol) in toluene (40ml) was heated at reflux temperature for 18 h. The mixture was cooled,filtered through a pad of Celite and then concentrated. The residue (10g) was dissolved in a mixture of THF (100 ml) and water (20 ml), cooledto 0° C. and N-bromosuccinimide (5.43 g, 30.52 mmol) was added over 20min. The resulting mixture was stirred for 0.5 h at the same temperatureand then concentrated to ca. 20 ml. The mixture was diluted in ethylacetate (300 ml), washed with water (100 ml×3), and dried (MgSO₄). Afterremoval of solvent, the crude product was purified by flash columnchromatography eluting with ethyl acetate/hexane (1:15 to 1:10) toafford 2.30 g (37%) of the title compound as an oil.

¹H-NMR (CDCl₃) δ: 8.49 (1H, br s), 8.01 (1H, d, J=8.1 Hz), 7.68-7.64(1H, m), 4.84 (2H, s), 2.44 (3H, s).

Step 2. [6-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]aceticAcid

Both of the diastereoisomers ofmethyl[6-chloro-1-ethoxycarbonyl-2-(5-methylpyridine-2-carbonyl)indolin-3-yl]acetate(step 2) were converted to the title compound, respectively, accordingto the procedure described in step 3 of Example 31.

MS (EI) m/z: 328 (M⁺). m.p.: 235-238° C. (recrystallized from ethylacetate). IR (KBr) ν: 3281, 1699, 1638, 1529, 1310, 1150, 797, 702 cm⁻¹.¹H-NMR (DMSO-d₆) δ: 12.26 (1H, br s), 8.68 (1H, br s), 8.04 (1H, d,J=8.1 Hz), 7.94 (1H, br d, J=9.1 Hz), 7.79 (1H, d, J=8.7 Hz), 7.74 (1H,br s), 7.11 (1H, br d, J=8.6 Hz), 4.10 (2H, s), 2.47 (3H, s). One signaldue to NH or COOH was not observed.

Example 33Methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate

A mixture of methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A, 675 mg, 1.92 mmol),2-bromoacetyl-4-chloropyridine hydrobromide* (907 mg, 2.88 mmol), andpotassium carbonate (2.65 g, 19.18 mmol) in acetone (20 ml) was heatedat reflux temperature for 4 h. The mixture was cooled and concentrated.The residue was diluted with ethyl acetate (150 ml) and washed withwater (70 ml×6). After drying (MgSO₄) and removal of solvent, the crudeproduct was purified by flash column chromatography eluting with ethylacetate/hexane (1:6-1:3) to afford 195 mg (28%) of the title compound(yellow solids) along with 264 mg (27%) ofmethyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate(brown crystals).

* 2-Bromoacetyl-4-chloropyridine hydrobromide was prepared as follows;

Methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate:

MS (EI) m/z: 362 (M⁺). ¹H-NMR (CDCl₃) δ: 12.09 (1H, br s), 8.62 (1H, d,J=5.3 Hz), 8.28 (1H, d, J=2.1 Hz), 7.57 (1H, d, J=8.6 Hz), 7.52 (1H, dd,J=2.0 and 5.3 Hz), 7.45 (1H, d, J=1.8 Hz), 7.08 (1H, dd, J=1.8 and 8.7Hz), 4.27 (2H, s), 3.75 (3H, s).

Methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate:

tlc: Rf=0.35 (ethyl acetate/hexane=1:2). MS (EI) m/z (intensity): 504(M⁺, 0.1), 363 (90), 335 (30), 304 (100), 275 (10), 223 (15).4-Chloro-2-pyridinecarbonitrile: To a mixture of4-chloropyridine-N-oxide (5.00 g, 38.6 mmol) and trimethylsilyl cycanide(4.84 g, 46.3 mmol) in dichloromethane (60 ml) cooled to 0° C. was addeddropwise N,N-dimethylcarbamoyl chloride (3.8 ml, 40.5 mmol). The mixturewas allowed to warm to ambient temperature and stirred for 16 h. Themixture was cooled to 0° C. and a 30% aqueous solution of potassiumcarbonate (100 ml) was added. The crude product was extracted withdichloromethane (100 ml×2), the organic extracts dried (MgSO₄) andevaporated to give 4-chloro-2-pyridinecarbonitrile (5.35 g, 100%).

¹H-NMR (CDCl₃) δ: 8.63 (1H, d, J=4.8 Hz), 7.72 (1H, d, J=2.6 Hz), 7.55(1H, dd, J=1.8, 5.1 Hz).

2-Acetyl-4-chloropyridine: To a solution of4-chloro-2-pyridinecarbonitrile (5.35 g, 38.6 mmol) in benzene (50 ml)and ether (50 ml) cooled to 0° C. was added dropwise over 20 min a 2Msolution of MeMgI in ether (23 ml, 46.3 mmol). After 0.5 h, the mixturewas allowed to warm to ambient temperature, and stirring continued for 2h. The mixture was cooled to 0° C. and 2M aqueous HCl (100 ml) added.The mixture was made basic with saturated aqueous sodium bicarbonate(˜80 ml) and the organic layer separated and dried (MgSO₄). Afterremoval of solvent, the residue was purified by flash chromatographyeluting with ethyl acetate/hexane (1:5) to afford 3.60 g (60%) of2-acetyl-4-chloropyridine.

¹H-NMR (DMSO-d₆) δ: 8.59 (1H, d, J=5.1 Hz), 8.04 (1H, d, J=1.8 Hz), 7.47(1H, dd, J=1.8, 5.1 Hz), 2.72 (3H, s).

2-Bromoacetyl-4-chloropyridine hydrobromide:2-(Bromoacetyl)-4-chloropyridine hydrobromide was prepared from2-acetyl-4-chloropyridine according to the method of H. McKennis, Jr.,L. B. Tumbull, E. R. Bowman, and E. Tamaki (in J. Org. Chem., 1963, 28,383-387).

¹H-NMR (DMSO-d₆) δ: 8.74 (1H, d, J=5.5 Hz), 8.05 (1H, d, J=1.8 Hz), 7.88(1H, dd, J=2.2 and 5.5 Hz), 5.02 (2H, s).

Example 34[6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

A suspension ofmethyl[6-chloro-2-[4-chloropyridine-2-carbonyl]-1H-indol-3-yl]acetate(Example 33, 195 mg, 0.537 mmol) in ethanol (20 ml) and 2N sodiumhydroxide (4 ml) was heated for 1 h at 50° C. After cooling to roomtemperature, 2N hydrochloric acid (4 ml) was added and the mixture wasconcentrated. The residue was diluted in ethyl acetate (100 ml), washedwith water (50 ml×2), and dried (MgSO₄). After removal of solvent, thecrystalline residue was recrystallized from ethyl acetate to afford 175mg (94%) of the title compound.

m.p.: 233-234° C. IR (KBr) ν: 3306, 1709, 1641, 1531, 1254, 1236, 741cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.20 (1H, br s), 12.16 (1H, br s), 8.80 (1H,d, J=5.4 Hz), 8.12 (1H, d, J=2.1 Hz), 7.90 (1H, dd, J=2.1, 5.3 Hz), 7.81(1H, d, J=8.7 Hz), 7.70 (1H, d, J=1.8 Hz), 7.13 (1H, dd, J=2.0, 8.7 Hz),4.07 (2H, s).

Example 35 [6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

Step 1.Methyl[6-chloro-1-ethoxycarbonyl-2-(pyridine-2-carbonyl)indolin-3-yl]acetate

The title compound were prepared according the procedure described instep 2 of Example 31 from methyltrans-4-chloro-2-(ethoxycarbonylamino)cinnamate (Example 31, step 1) and2-bromoacetylpyridine hydrobromide (H. McKennis et al., J. Org. Chem.,1963, 387.).

tlc: Rf=0.3 (ethyl acetate/hexane=1:3).

Step 2. [6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound were prepared according the procedure described instep 3 of Example 31 frommethyl[6-chloro-1-ethoxycarbonyl-2-(pyidine-2-carbonyl)indolin-3-yl]acetate(step 1).

m.p.: 210° C. (decomposed). IR (KBr) ν: 3280, 1697, 1643, 1531, 1234,1150 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.22 (1H, s), 8.84 (1H, d, J=4.9 Hz),8.15-8.05 (2H, m), 7.85-7.65 (3H, m), 7.11 (1H, dd, J=1.9, 8.7 Hz), 4.04(2H, s).

Example 36[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

Step 1. Methyl trans-5-Chloro-2-nitrocinnamate

A mixture of the 5-chloro-2-nitrobenzaldehyde (9.68 g, 52.16 mmol) andmethyl(triphenylphophoranylidene)acetate (18.31 g, 54.77 mmol) intoluene (200 ml) was heated at reflux temperature for 2 h. The mixturewas concentrated and the crystalline residue was purified by flashcolumn chromatography eluting with ethyl acetate/hexane (1:5) to affordcrystals. Recrystallizaion from ethyl acetate/hexane gave 7.54 g (60%)of the title compound as pale yellow solids.

¹H-NMR (CDCl₃) δ: 8.09 (1H, d, J=15.8 Hz), 8.04 (1H, d, J=8.7 Hz), 7.60(1H, d, J=2.1 Hz), 7.51 (1H, dd, J=2.1, 8.7 Hz), 6.36 (1H, d, J=15.8Hz), 3.84 (3H, s).

Step 2. Methyl trans-2-Amino-5-chlorocinnamate

A mixture of methyl trans-5-chloro-2-nitrocinnamate (step 1, 3.00 g,12.42 mmol), iron powder (3.65 g, 62.08 mmol), ammonium chloride (332mg, 6.21 mmol), ethanol (60 ml) and water (10 ml) was heated at refluxtemperature for 2 h. The mixture was cooled and filtered through a padof Celite. The filtrate was concentrated. The residue was diluted withethyl acetate (200 ml) and washed with water (100 ml×2). After drying(MgSO₄), removal of solvent gave 2.57 g (98%) of the title compound ascrystals.

¹H-NMR (CDCl₃) δ: 7.73 (1H, d, J=15.8 Hz), 7.34 (1H, d, J=2.5 Hz), 7.12(1H, dd, J=2.3, 8.6 Hz), 6.64 (1H, d, J=8.6 Hz), 6.35 (1H, d, J=15.8Hz), 3.95 (2H, br s), 3.81 (3H, s).

Step 3. Methyl trans-5-Chloro-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-2-amino-5-chlorocinnamate (step 2).

¹H-NMR (CDCl₃) δ: 7.72-7.67 (2H, m), 7.58-7.51 (1H, m), 7.47-7.40 (4H,m), 7.36 (1H, d, J=8.6 Hz), 7.31 (1H, dd, J=2.1, 8.6 Hz), 6.14 (1H, d,J=15.8 Hz), 3.78 (3H, s). One signal due to NH was not observed.

Step 4.Methyl[5-chloro-2-(4-methylpyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate

The title compound was prepared according to the procedure described instep 2 of Example 8 (Method A) from methyltrans-5-chloro-2-(phenylsulfonylamino)cinnamate (step 3) and2-bromoacetyl-4-methylpyridine hydrobromide (F. H. Case et al., J. Am.Chem. Soc., 1956, 78, 5842).

tlc: Rf=0.32 (ethyl acetate/hexane=1:2)

Step 5. [5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described instep 3 of Example 31 frommethyl[5-chloro-2-(4-methylpyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate(step 4).

MS (EI) m/z: 328 (M⁺). m.p.: 230-231° C. (recrystallized from ethylacetate). IR (KBr) ν: 3292, 1699, 1597, 1533, 1282, 1198, 1059, 802, 704cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.26 (1H, br s), 8.69 (1H, d, J=5.1 Hz), 7.93(1H, br s), 7.82 (1H, d, J=2.0 Hz), 7.66 (1H, d, J=8.7 Hz), 7.56 (1H, brd, J=4.9 Hz), 7.31 (1H, dd, J=2.0, 8.7 Hz), 4.02 (2H, s), 2.46 (3H, s).One signal due to NH or COOH was not observed.

Example 37Methyl[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

Step 1.Methyl[5-chloro-2-(6-methylpyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate

The title compound was prepared according to the procedure described instep 2 of Example 8 (Method A) from methyltrans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and2-bromoacetyl-6-methylpyridine hydrobromide (H. Erlenmeyer, J. Jenni,and B. Prijs, J. Med. Pharm. Chem., 1961, 3, 561-566).

tlc: Rf=0.39 (ethyl acetate/hexane=2:3).

Step 2.Methyl[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described instep 3 of Example 8 (Method A) frommethyl[5-chloro-2-(6-methylpyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate(step 1).

¹H-NMR (CDCl₃) δ: 12.62 (1H, br s), 8.15 (1H, d, J=7.9 Hz), 7.84 (1H, t,J=7.7 Hz), 7.67 (1H, d, J=1.8 Hz), 7.43 (1H, d, J=8.9 Hz), 7.40 (1H, d,J=7.7 Hz), 7.32 (1H, dd, J=2.0, 8.7 Hz), 4.28 (2H, s), 3.73 (3H, s),2.76 (3H, s).

Example 38[5-Chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 34 frommethyl[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate.

MS (EI) m/z: 328 (M⁺). m.p.: 225-226° C. (recrystallized from ethylacetate). IR (KBr) ν: 1705, 1636, 1529, 1333, 1236, 1180, 1061, 669 cm¹.¹H-NMR (DMSO-d₆) δ: 12.13 (1H, br s), 12.09 (1H, br s), 7.99 (1H, t,J=7.7 Hz), 7.87 (1H, d, J=7.7 Hz), 7.84 (1H, d, J=2.0 Hz), 7.66 (1H, d,J=8.9 Hz), 7.59 (1H, d, J=7.6 Hz), 7.33 (1H, dd, J=2.0, 8.9 Hz), 4.03(2H, s), 2.69 (3H, s).

Example 39[6-Chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic Acid

Step 1.Methyl[6-chloro-1-ethoxycarbonyl-2-(1-methylimidazole-2-carbonyl)indolin-3-yl]acetate

The title compound was prepared according to the procedure described instep 2 of Example 31 from methyltrans-4-chloro-2-(ethoxycarbonylamino)cinnamate (Example 31, step 1) and2-bromoacetyl-1-methylimidazole hydrobromide.*

* 2-Bromoacetyl-1-methylimidazole hydrobromide was prepared as follows;

MS (EI) m/z: 405 (M⁺).

To a stirred suspension of 2-acetyl-1-methylimidazole (D. H. Davis, J.Hall, and E. H. Smith, J. Chem. Soc. Perkin trans. 1, 1991, 2691., 3.0g, 26.8 mmol) in 25% HBr—AcOH was added dropwise a solution of bromine(4.7 g, 29.5 mmol) with ice-cooling. After stirring for 0.5 h, themixture was allowed to warm to room temperature and the stirring wascontinued for an additional 1 h. To the mixture was added diethyl ether(150 ml) and the mixture was cooled with ice-bath. The precipitates werecollected by filtration to give 5.2 g (66%) of the title compound as apale yellow powder.

¹H-NMR (DMSO-d₆) d: 7.61 (1H, s), 7.27 (1H, s), 4.68 (2H, s), 3.81 (3H,s).

Step 2. [6-Chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described instep 3 of Example 31 from[6-chloro-1-ethoxycarbonyl-2-(1-methylimidazole-2-carbonyl)indolin-3-yl]acetate(step 1).

m.p.: 236° C. (decomposed). MS (EI) m/z: 317 (M⁺). IR (KBr) ν: 3238,1695, 1630, 1537, 1402, 1229, 1146 cm⁻¹. ¹H-NMR (CDCl₃+DMSO-d₆) δ: 12.30(1H, s), 7.65 (1H, d, J=8.7 Hz), 7.50 (1H, d, J=1.8 Hz), 7.42 (1H, s),7.28-7.23 (1H, m), 7.16 (1H, s), 7.09 (1H, dd, J=1.8, 8.6 Hz), 4.25 (2H,s), 4.13 (3H, s).

Example 40 Methyl[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetate

Step 1.Methyl[5-chloro-1-phenylsulfonyl-2-(thiazole-2-carbonyl)indolin-3-yl]acetate

The title compound was prepared according to the procedure described instep 2 of Example 8 (Method A) from methyltrans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and2-bromoacetylthiazole hydrobromide (A. Dondoni, A. Marra, and P. Merino,J. Am. Chem. Soc., 1994, 116, 3324).

tlc: Rf=0.07 (ethyl acetate/hexane=1:2).

Step 2. Methyl[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described instep 3 of Example 8 (Method A) frommethyl[5-chloro-1-phenylsulfonyl-2-(thiazole-2-carbonyl)indolin-3-yl]acetate(step 1).

¹H-NMR (CDCl₃) δ: 11.78 (1H, br s), 8.12 (1H, d, J=3.1 Hz), 7.75 (1H, d,J=3.1 Hz), 7.68 (1H, d, J=1.8 Hz), 7.44 (1H, d, J=8.7 Hz), 7.34 (1H, dd,J=2.0, 8.9 Hz), 4.29 (2H, s), 3.74 (3H, s).

Example 41 [5-Chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[5-chloro-1-phenylsulfonyl-2-(thiazole-2-carbonyl)-1H-indol-3-yl)acetate(step 2).

MS (EI) m/z: 320 (M⁺). m.p.; 230-231IC (recrystallized from ethylacetate). IR (KBr) ν: 3302, 1703, 1636, 1541, 1387, 1335, 1267, 1232,1186, 1003, 766 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.23 (1H, br s), 12.10 (1H,br s), 8.33 (1H, d, J=3.1 Hz), 8.31 (1H, d, J=3.1 Hz), 7.89 (1H, d,J=2.0 Hz), 7.77 (1H, d, J=8.9 Hz), 7.36 (1H, dd, J=2.0, 8.7 Hz), 4.17(2H, s).

Example 42 Methyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate

A mixture of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2,50 mg, 0.16 mmol) and 10% HCl in methanol (3 ml) was stirred for 3 h atroom temperature. The mixture was concentrated and the residue waspurified by flash column chromatography eluting with ethylacetate/hexane (1:5) to afford 23 mg (44%) of the title compound aswhite solids.

m.p.: 134-137° C. IR (KBr) ν: 1735, 1620, 1529, 1434, 1325, 1147, 1013,945 cm⁻¹. ¹H-NMR (CDCl₃) δ: 8.96 (1H, br s), 7.85-7.74 (2H, m),7.66-7.47 (4H, m), 7.38 (1H, d, J=1.8 Hz), 7.15 (1H, dd, J=1.8, 8.6 Hz),3.18 (2H, s), 3.65 (3H, s).

Example 43 (2-Benzoyl-6-chloro-1H-indol-3-yl)-N,N-dimethylacetamide

To a solution of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example2, 140 mg, 0.45 mmol), dimethylamine hydrochloride (45 mg, 0.54 mmol)and triethylamine (0.1 ml, 0.54 mmol) in DMF (2 ml) at 0° C. was addeddiethyl phosphorocyanidate (DEPC, 0.1 ml, 0.54 mmol). The mixture wasthen stirred at room temperature for 1 h. The mixture was poured intowater (20 ml) and extracted with diethyl ether (50 ml×2). The organicextracts were washed with water (30 ml×2), dried (MgSO₄) andconcentraied. The residual solids were recrystallized from ethylacetate/hexane to afford 50 mg (33%) of the title compound.

m.p.: 190-193° C. (recrystallized from ethyl acetate/hexane). IR (KBr)ν: 1631, 1232, 1007, 908 cm⁻¹. ¹H-NMR (CDCl₃) δ: 11.72 (1H, br s),7.72-7.64 (4H, m), 7.60-7.52 (2H, m), 7.45 (1H, d, J=1.2 Hz), 7.08 (1H,d, J=8.6 Hz), 3.32 (2H, s), 2.80 (3H, s), 2.76 (3H, s).

Example 44 (2-Benzoyl-6-chloro-1H-indol-3-yl)-N-methylacetamide

The title compound was prepared according to the procedure described inExample 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example2) and methylamine hydrochloride.

m.p.: 242-246° C. (recrystallized from ethyl acetate/hexane). IR (KBr)ν: 1618, 1527, 1409, 1325 cm⁻¹. ¹H-NMR (CDCl₃) δ: 11.71 (1H, br s),7.82-7.75 (2H, m), 7.62-7.52 (5H, m), 7.49-7.46 (1H, m), 7.15-7.08 (1H,m), 3.64 (2H, s), 3.31 (3H, s).

Example 45 (2-Benzoyl-6-chloro-1H-indol-3-yl)acetamide

The title compound was prepared according to the procedure described inExample 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example2) and a solution of ammonia in THF.

m.p.: 234-237° C. IR (KBr) ν: 1665, 1618, 1566, 1523, 1325, 1259, 943cm⁻¹. ¹H-NMR (CDCl₃) δ: 11.66 (1H, br s), 7.82-7.75 (2H, m), 7.74-7.65(2H, m), 7.62-7.53 (2H, m), 7.46 (1H, d, J=1.8 Hz), 7.27 (1H, br s),7.12 (1H, dd, J=1.8, 8.6 Hz), 6.85 (1H, br s), 3.63 (2H, s).

Example 46(2-Benzoyl-6-chloro-1H-indol-3-yl)-N-methoxy-N-methylacetamide

The title compound was prepared according to the procedure described inExample 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example2) and N,O-dimethylhydroxylamine hydrochloride.

m.p.: 109.9-112.2° C. (decomposed). IR (KBr) ν: 3179, 2970, 2937, 1634,1599, 1570 cm⁻¹. ¹H-NMR (CDCl₃) δ: 9.20-8.90 (1H, m), 7.84-7.75 (2H, m),7.66-7.45 (4H, m), 7.33 (1H, d, J=1.3 Hz), 7.12 (1H, dd, J=8.6, 1.8 Hz),3.94 (2H, s), 3.51 (3H, s), 3.13 (3H, s).

Example 47 2-(2-Benzoyl-6-chloro-1H-indol-3-yl)-1-piperidino-1-ethanone

Step 1. 7-Chloro-1-phenyl-9H-pyrano[3,4-b]indole-3-one

A solution of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2,200 mg, 0.64 mmol), diethyl phosphorocyanidate (DEPC, 0.12 ml, 0.76mmol) and triethylamine (0.11 ml, 0.76 mmol) in DMF (3.0 ml) was stirredat room temperature for 5 min. The mixture was then poured into water(20 ml) and the orange precipitates were collected by filtration to give20 mg (11%) of the title compound as orange solids.

¹H-NMR (CDCl₃) δ: 10.79 (1H, br s), 8.10 (1H, d, J=8.4 Hz), 7.93-7.84(2H, m), 7.67-7.50 (3H, m), 7.29 (1H, s), 7.13 (1H, d, J=8.4 Hz), 6.87(1H, s).

Step 2. 2-(2-Benzoyl-6-chloro-1H-indol-3-yl)-1-piperidino-1-ethanone

A mixture of 7-chloro-1-phenyl-9H-pyrano[3,4-b]indole-3-one (step 1,0.30 g, 1.0 mmol), and piperidine (1.0 ml, 10 mmol) in methanol (20 ml)was heated under reflux temperature for 2 h. After cooling down to rt,the yellow mixture was concentrated and the residual solids wererecrystallized from methanol/hexane to give 0.12 g (32%) of the titlecompound.

m.p.: 223-224° C. IR (KBr) ν: 3310, 2928, 1655, 1570, 1533, 1447, 1323,1256, 1225, 1059, 945, 858, 737, 700 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.7 (1H,br s), 7.74-7.63 (4H, m), 7.55 (2H, t, J=8.7 Hz), 7.46 (1H, d, J=1.8Hz), 7.09 (1H, dd, J=8.7, 1.8 Hz), 3.80 (2H, s), 3.45-3.20 (4H, m),1.55-1.20 (6H, m).

Example 482-(2-Benzoyl-6-chloro-1H-indol-3-yl)-N-(4-methyl-1-piperazinyl)-1-ethanone

The title compound was prepared according to the procedure described inExample 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example2) and 1-methylpiperazine.

m.p.: 184-185° C. (recrystallized from methanol/hexane). IR (KBr) ν:2939, 2795, 1634, 1531, 1435, 1325, 1229, 1144, 1001, 737, 700 cm⁻¹.¹H-NMR (CDCl₃) δ: 9.37 (1H, br s), 7.78-7.75 (1H, m), 7.73 (1H, d, J=1.5Hz), 7.62-7.52 (2H, m), 7.52-7.43 (2H, m), 7.18-7.10 (1H, m), 7.10-7.02(1H, m), 3.81 (2H, s), 3.54 (2H, br s), 3.36 (2H, t, J=4.8 Hz),2.36-2.22 (4H, m), 2.28 (3H, s).

Example 49 (2-Benzoyl-6-chloro-1H-indol-3-yl)-N-(2-cyanoethyl)acetamide

The title compound was prepared according to the procedure described inExample 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example2) and aminopropionitrile.

m.p.: 233-233.5° C. (recrystallized from methanol/hexane). ¹H-NMR(DMSO-d₆) δ: 11.7 (1H, br s), 8.16 (1H, t, J=6.3 Hz), 7.81-7.75 (2H, m),7.72-7.64 (2H, m), 7.62-7.53 (2H, m), 7.47 (1H, d, J=1.9 Hz), 7.10 (1H,dd, J=8.7, 1.9 Hz), 3.67 (2H, s), 3.23 (2H, q, J=6.3 Hz), 2.58 (2H, t,J=6.3 Hz).

Example 50(2-Benzoyl-6-chloro-1H-indol-3-yl)-N-(2-hydroxyethyl)acetamide

The title compound was prepared according to the procedure described inExample 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example2) and 2-aminoethanol.

m.p.: 178-179.5° C. (recrystallized from methanol/hexane). ¹H-NMR(DMSO-d₆) δ: 11.7 (1H, br s), 7.84-7.75 (3H, m), 7.72-7.64 (2H, m),7.61-7.52 (2H, m), 7.46 (1H, d, J=2.0 Hz), 7.11 (1H, dd, J=8.6, 2.0 Hz),3.64 (2H, s), 3.38-3.30 (3H, m), 3.06 (2H, q, J=5.9 Hz).

Example 51 2-(2-Benzoyl-6-chloro-1H-indol-3-yl)-1-morpholino-1-ethanone

The title compound was prepared according to the procedure described inExample 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example2) and morpholine.

m.p.: 187.7-189.5° C. IR (KBr) ν: 3339, 2964, 2849, 1653, 1612, 1568cm⁻¹. ¹H-NMR (CDCl₃) δ: 9.08-8.92 (1H, m), 7.81-7.72 (2H, m), 7.69-7.58(2H, m), 7.56-7.47 (2H, m), 7.29 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=8.6,1.8 Hz), 3.87 (2H, s), 3.67-3.46 (6H, m), 3.41-3.31 (2H, m).

Example 52 [2-(4-Chlorobenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 2-(4-Chlorobenzoyl)-1-(phenylsulfonyl)indole

To a solution of 1-(phenylsulfonyl)indole (500 mg, 1.94 mmol) in THF (5ml) was added dropwise tert-butyllithium (1.4 ml, 2.33 mmol) undernitrogen atmosphere at −78° C. The yellow solution was cannulateddirectly into a solution of p-chlorobenzoyl chloride (0.3 ml, 2.33 mmol)in THF (3 ml) cooled to −78° C. The reaction mixture was stirred at −78°C. for 2 h. The mixture was quenched with saurated ammonium chloride andextracted with ethyl acetate (100 ml). The organic layer was washed withwater (50 ml), brine (50 ml) and dried (MgSO₄). After removal ofsolvent, the crude product was purified by flash column chromatographyeluting with hexane/ethyl acetate (10:1) to afford 339 mg (44.1%) of thetitle compound as yellow amorphous solids.

¹H-NMR (CDCl₃) δ: 8.13 (1H, d, J=8.4 Hz), 8.04-8.00 (2H, m), 7.93-7.90(2H, m), 7.58-7.44 (7H, m), 7.30 (1H, t, J=7.4 Hz), 6.95 (1H, s).

Step 2. 2-(4-Chlorobenzoyl)indole

A mixture of 2-(4-chlorobenzoyl)-1-(phenylsulfonyl)indole (step 1, 334mg, 0.84 mmol) and 2N sodium hydroxide (1.5 ml, 2.78 mmol) in ethanol (5ml) was heated at reflux temperature for 15 min. The mixture wasconcentrated and the residue was diluted with ethyl acetate (100 ml).The organic layer was washed with water and dried (MgSO₄), andconcentrated to afford 211 mg (98.2%) of the title compound as yellowsolids.

¹H-NMR (CDCl₃) δ: 9.45 (1H, br.s), 7.97-7.92 (2H, m), 7.74-7.70 (1H, m),7.54-7.47 (3H, m), 7.42-7.36 (1H, m), 7.21-7.13 (2H, m).

Step 3. Diethyl α-Acetoxy-[2-(4-chlorobenzoyl)-1H-indol-3-yl)]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) employing 2-(4-chlorobenzoyl)indole (step2).

¹H-NMR (CDCl₃) δ: 8.94 (1H, br.s), 7.90 (1H, d, J=8.4 Hz), 7.81-7.77(2H, m), 7.43-7.36 (3H, m), 7.32-7.26 (1H, m), 7.22-7.16 (1H, m),4.27-4.14 (4H, m), 1.75 (3H, s), 1.29-1.16 (6H, m).

Step 4. Diethyl[2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) employing diethylα-acetoxy-[2-(4-chlorobenzoyl)-1H-indol-3-yl)]malonate (step 3).

¹H-NMR (CDCl₃) δ: 8.73 (1H, br.s), 7.85-7.82 (1H, m), 7.79-7.76 (2H, m),7.52-7.46 (2H, m), 7.39-7.37 (1H, m), 7.26-7.19 (2H, m), 5.27 (1H, s),4.26-4.16 (4H, m), 1.26-1.21 (6H, m).

Step 5. [2-(4-Chlorobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) employingdiethyl[2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate (step 4).

m.p.: 221-224° C. (recrystallized from ethyl acetate/hexane). IR (KBr)ν: 3321, 1697, 1607, 1576, 1529, 1433, 1408, 1339, 1263, 1223, 1202cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.62 (1H, s), 7.79-7.75 (2H, m), 7.71-7.63(3H, m), 7.46 (1H, d, J=8.2 Hz), 7.35-7.29 (1H, m), 7.14-7.08 (1H, m),3.84 (2H, s).

Example 53 [6-Chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic Acid

Step 1. 6-Chloro-2-(2-furylcarbonyl)-1-(phenylsulfonyl)indole

The title compound was prepared according the procedure described instep 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole(step 1 of Example 2, Method B) and 2-furoyl chloride.

¹H-NMR (CDCl₃) δ: 8.11-8.19 (3H, m), 7.73-7.74 (1H, m), 7.51-7.65 (4H,m), 7.27-7.31 (2H, m), 7.10 (1H, s), 6.62-6.64 (1H, m).

Step 2. 6-Chloro-2-(2-furylcarbonyl)indole

The title compound was prepared according to the procedure described instep 3 of Example 2 (Method B) from6-chloro-2-(2-furylcarbonyl)-1-(phenylsulfonyl)indole (step 1).

¹H-NMR (CDCl₃) δ: 9.33 (1H, br s), 7.65-7.73 (3H, m), 7.46-7.48 (2H, m),7.12-7.16 (1H, m), 6.64-6.66 (1H, m).

Step 3. Diethylα-Acetoxy[6-chloro-2-(2-furylcarbonyl)indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 6-chloro-2-(2-furylcarbonyl)indole(step 2).

¹H-NMR (CDCl₃) δ: 9.60 (1H, br s), 7.76 (1H, d, J=8.9 Hz), 7.62-7.63(1H, m), 7.43 (1H, d, J=1.3 Hz), 7.28-7.29 (1H, m), 7.13 (1H, dd, J=1.8Hz, 8.7 Hz), 6.59 (1H, dd, J=1.6 Hz, 3.5 Hz), 4.18-4.32 (4H, m), 1.88(3H, s), 1.18-1.28 (6H, m).

Step 4. Diethyl[6-chloro-2-(2-furylcarbonyl)indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[6-chloro-2-(2-furylcarbonyl)indol-3-yl]malonate (step 3).

¹H-NMR (CDCl₃) δ: 9.83 (1H, br s), 7.67 (1H, t, J=0.8 Hz), 7.63 (1H, d,J=8.9 Hz), 7.40 (1H, d, J=3.6 Hz), 7.30 (1H, d, J=1.8 Hz), 7.01 (1H, dd,J=1.8 Hz, 8.9 Hz), 6.62 (1H, dd, J=1.6 Hz. 2.1 Hz), 6.19 (1H, s),4.20-4.32 (4H, m), 1.27 (6H, t, J=7.3 Hz).

Step 5. [6-Chloro-2-(2-furylcarbonyl)indol-3-yl]acetic Acid.

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(2-furylcarbonyl)indol-3-yl]malonate (step 4).

¹H-NMR (DMSO-d₆) δ: 12.22 (1H, br s), 11.76 (1H, br s), 8.13 (1H, d,J=1.0 Hz), 7.75 (1H, d, J=8.6 Hz), 7.56 (1H, d, J=1.8 Hz), 7.48 (1H, d,J=3.6 Hz), 7.14 (1H, dd, J=1.8 Hz, 8.6 Hz), 6.85 (1H, dd, J=1.8 Hz, 3.6Hz), 4.02 (2H, s).

Example 54 [6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic Acid

Step 1. 6-Chloro-2-cyclohexanecarbonyl-1-(phenylsulfonyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole(step 1 of Example 2, Method B) and cyclohexanecarbonyl chloride.

tlc: Rf=0.4 (ethyl acetate/hexane=1:4).

Step 2. 6-Chloro-2-(cyclohexanecarbonyl)indole

The title compound was prepared according to the procedure described instep 3 of Example 2 (Method B) from6-chloro-2-cyclohexanecarbonyl-1-(phenylsulfonyl)indole (step 1).

¹H-NMR (CDCl₃) δ: 10.08 (1H, br s), 8.08-7.04 (4H, m), 2.28-1.20 (1H,m).

Step 3. Diethylα-Acetoxy-[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from6-chloro-2-(cyclohexanecarbonyl)indole (step 2).

¹H-NMR (CDCl₃) δ: 8.94 (1H, br s), 8.12-7.09 (3H, m), 4.34-4.21 (4H, m),2.20 (3H, s), 1.81-1.20 (17H, m).

Step 4. Diethyl[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[6-chloro-2-(cyclohexanecarbony)-1H-indol-3-yl]malonate (step3).

¹H-NMR (CDCl₃) δ: 8.90 (1H, br s), 7.72 (1H, d, J=8.72 Hz), 7.36-7.09(2H, m), 5.70 (1H, s), 4.28-4.19 (4H, m), 1.91-1.22 (17H, m).

Step 5. [6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]malonate (step4).

m.p.: 206-209° C. IR (KBr) ν: 3314, 2924, 2856, 1734, 1650, 1537, 1396,1248, cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.78 (1H, s), 7.71 (1H, d, J=8.64 Hz),7.46-7.07 (2H, m), 4.01 (2H, s), 1.78-1.16 (11H).

Example 55 Methyl[6-chloro-2-(4-methoxybenzoyl-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 8 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8) and 4-methoxyphenacyl bromide.

¹H-NMR (CDCl₃) δ: 8.85 (1H, s), 7.82 (2H, d, J=8.9 Hz), 7.56 (1H, d,J=8.6 Hz), 7.40 (1H, d, J=1.8 Hz), 7.15 (1H, dd, J=1.8, 8.6 Hz), 6.99(2H, d, J=8.6 Hz), 3.90 (3H, s), 3.86 (2H, s), 3.67 (3H, s).

Example 56 [6-Chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate (step 1).

m.p.: 187-190° C. ¹H-NMR (DMSO-d₆) δ: 11.72 (1H, s), 7.78 (2H, d, J=8.7Hz), 7.70 (1H, d, J=8.6 Hz), 7.49-7.45 (1H, m), 7.15-7.07 (3H, m), 3.87(3H, s), 3.81 (2H, s).

Example 57Methyl[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

A mixture of methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A, 700 mg, 1.99 mmol),2-bromoacetyl-4-ethylpyridine* (545 mg, 2.39 mmol), potassium carbonate(1.37 g, 13.9 mmol) and acetone (20 ml) was stirred at room temperature.After stirring for 3 h, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.6 ml,3.98 mmol) was added. The resulting mixture was stirred for anadditional 19 h and then concentrated. The residue was diluted withdichloromethane (200 ml) and washed with water (100 ml×2). The organiclayer was dried (MgSO₄) and concentrated. The residue was purified byflash column chromatography eluting with ethylacetate/hexane/dichloromethane (1:4:1) to give the title compoundincluding impurity. The crude product was washed with ethyl acetate togive 297 mg (42%) of the title compound as yellow solids.

* 2-Bromoacetyl-4-ethylpyridine was prepared as follows;

¹H-NMR (CDCl₃) δ: 12.52 (1H, br s), 8.64 (1H, d, J=4.9 Hz), 8.21 (1H, brs), 7.62 (1H, d, J=8.7 Hz), 7.52 (1H, d, J=1.8 Hz), 7.39-7.35 (1H, m),7.13 (1H, dd, J=1.8, 8.6 Hz), 4.31 (2H, s), 3.73 (3H, s), 2.78 (2H, q,J=7.6 Hz), 1.32 (3H, t, J=7.6 Hz).

To a solution of 2-acetyl-4-ethylpyridine (E. C. Constable et al., J.Am. Chem. Soc., 1997, 119, 5606, 8.37 g, 56.1 mmol) in 25% hydrobromicacid-acetic acid (150 ml) was added dropwise a solution of bromine (9.86g, 61.7 mmol) in acetic acid (30 ml) with ice-cooling. The mixture wasallowed to warm to room temperature and stirred for 2 h. Diethyl ether(500 ml) was added to the mixture and the resulting mixture was cooledwith an ice-bath. A brown oil, separated out from the solution, wascollected by decantation. The oil was treated with saturated aqueoussodium bicarbonate (50 ml) and extracted with diethyl ether (300 ml).The organic layer was dried (MgSO₄) and concentrated to give 15.3 g(88%) of the title compound.

¹H-NMR (CDCl₃) δ: 8.56 (1H, d, J=5.1 Hz), 7.95 (1H, br s), 7.36-7.34(1H, m), 4.86 (2H, s), 2.74 (2H, q, J=7.7 Hz), 1.29 (3H, t, J=7.6 Hz).

Example 58 [6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticAcid

A yellow suspension ofmethyl[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 57, 297 mg, 0.83 mmol) in 2N aqueous sodium hydroxide (2.5 ml)and ethanol (20 ml) was heated at reflux temperature for 3 h. Aftercooling to room temperature, the mixture was neutralized with 2N aqueoushydrochloric acid (2.5 ml) and concentrated. The residue was dilutedwith THF (150 ml), dried (MgSO₄) and concentrated. The residual solidswere recrystallization from ethyl acetate to give 251 mg (88%) of thetitle compound as yellow solids.

MS (EI) m/z: 342 (M⁺). m.p.: 215-216° C. (decomposition). IR (KBr) ν:3206, 1707, 1643, 1595, 1535, 1421, 1227, 1192, 1140, 912, 777 cm⁻¹.¹H-NMR (DMSO-d₆) δ: 12.30 (1H, br s), 12.18 (1H, br s), 8.73 (1H, d,J=4.9 Hz), 7.98 (1H, br s), 7.79 (1H, d, J=8.7 Hz), 7.74 (1H, d, J=1.8Hz), 7.62 (1H, br d, J=5.1 Hz), 7.12 (1H, dd, J=1.8, 8.6 Hz), 4.08 (2H,s), 2.78 (2H, q, J=7.7 Hz), 1.26 (3H, t, J=7.7 Hz).

Example 59Methyl[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-4-ethylpyridine (Preparation isdescribed in Example 57).

¹H-NMR (CDCl₃) δ: 12.57 (1H, br s), 8.65 (1H, d, J=5.1 Hz), 8.21 (1H, brs), 7.68 (1H, br s), 7.45 (1H, d, J=8.9 Hz), 7.40-7.36 (1H, m), 7.31(1H, dd, J=2.0, 8.7 Hz), 4.28 (2H, s), 3.74 (3H, s), 2.78 (2H, q, J=7.7Hz), 1.32 (3H, t, J=7.7 Hz).

Example 60 [5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 59).

MS (EI) m/z: 342 (M⁺). m.p.: 217-218° C. IR (KBr) ν: 3269, 1705, 1643,1595, 1533, 1418, 1335, 1225, 1200, 1059, 779 cm⁻¹. ¹H-NMR (DMSO-d₆) δ:12.33 (1H, br s), 8.73 (1H, d, J=4.9 Hz), 7.98 (1H, br s), 7.86 (1H, d,J=2.0 Hz), 7.69 (1H, d, J=8.9 Hz), 7.61 (1N, dd, J=4.8, 1.6 Hz), 7.33(1H, dd, J=2.0, 8.7 Hz), 4.07 (2H, s), 2.78 (2H, q, J=7.6 Hz), 1.26 (3H,t, J=7.6 Hz).

Example 61Methyl[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 2-bromoacetyl-4-isopropylpyridine*.

* 2-Bromoacetyl-4-isopropylpyridine was prepared from2-acetyl-4-isopropylpyridine (K. Ishihama et al., J. Agric. Food Chem.,1992, 40, 1647) according to the procedure for preparing2-bromoacetyl-4-ethylpyridine described in Example 57.

¹H-NMR (CDCl₃) δ: 12.53 (1H, br s), 8.65 (1H, d, J=4.9 Hz), 8.24 (1H, d,J=1.6 Hz), 7.62 (1H, d, J=8.7 Hz), 7.52 (1H, d, J=1.6 Hz), 7.40 (1H, dd,J=1.8, 4.9 Hz), 7.13 (1H, dd, J=1.8, 8.7 Hz), 4.30 (2H, s), 3.73 (3H,s), 2.97-3.07 (1H, m), 1.32 (6H, d, J=6.9 Hz). ¹H-NMR (CDCl₃) δ: 8.57(1H, d, J=5.8 Hz), 7.97-7.98 (1H, m), 7.36-7.38 (1H, m), 4.86 (2H, s),2.94-3.04 (1H, m), 1.27-1.32 (6H, m).

Example 62[6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 61).

m.p.: 194-196° C. IR (KBr) ν: 3244, 2965, 1692, 1647, 1597, 1537, 1254,1200, 1178, 1150, 764 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.28 (1H, br s), 8.74(1H, d, J=5.3 Hz), 8.01 (1H, s), 7.80 (1H, d, J=8.9 Hz), 7.74 (1H, d,J=1.6 Hz), 7.64-7.66 (1H, m), 7.12 (1H, dd, J=1.8, 8.6 Hz), 4.08 (2H,s), 3.02-3.13 (1H, m), 1.28 (6H, d, J=6.9 Hz).

Example 63Methyl[5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-4-isopropylpyridine (Preparationis described in Example 61).

¹H-NMR (CDCl₃) δ: 12.57 (1H, br s), 8.65 (1H, d, J=5.1 Hz), 8.24 (1H, d,J=1.6 Hz), 7.67 (1H, d, J=2.0 Hz), 7.44 (1H, d, J=8.2 Hz), 7.40 (1H, dd,J=1.8, 4.9 Hz), 7.31 (1H, dd, J=2.0, 8.7 Hz), 4.28 (2H, s), 3.74 (3H,s), 2.97-3.07 (1H, m), 1.32 (6H, d, J=6.9 Hz).

Example 64[5-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 63).

MS (EI) m/z: 356 (M⁺). m.p.: 227-228° C. IR (KBr) ν: 2964, 1703, 1643,1595, 1537, 1202, 1059, 768 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.32 (1H, br s),12.15 (1H, br s), 8.74 (1H, d, J=4.9 Hz), 8.00 (1H, s), 7.86 (1H, s),7.64-7.71 (2H, m), 7.31-7.35 (1H, m), 4.08 (2H, s), 3.03-3.13 (1H, m),1.28 (6H, d, J=6.9 Hz).

Example 65Methyl[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 2-bromoacetyl-4-propylpyridinehydrobromide*.

* 2-Bromoacetyl-4-propylpyridine hydrobromide was prepared as follows;

¹H-NMR (CDCl₃) δ: 12.53 (1H, br s), 8.64 (1H, d, J=4.9 Hz), 8.19 (1H,s), 7.62 (1H, d, J=8.7 Hz), 7.53 (1H, d, J=1.6 Hz), 7.35-7.37 (1H, m),7.13 (1H, dd, J=1.8, 8.7 Hz), 4.31 (2H, s), 3.73 (3H, s), 2.71 (2H, t,J=7.3 Hz), 1.69-1.77 (2H, m), 0.98 (3H, t, J=7.3 Hz).

4-Propyl-2-pyridinecarbonitrile:

The title compound was prepared from 4-propylpyrinine-N-oxide (S.Ghersetti et al., J. Heterocycl. Chem., 1969, 6, 859) according to theprocedure for preparing 4-chloro-2-pyridinecarbonitrile described inExample 33.

¹H-NMR (CDCl₃) δ: 8.59 (1H, d, J=5.1 Hz), 7.53 (1H, s), 7.32-7.34 (1H,m), 2.66 (2H, t, J=7.3 Hz), 1.62-1.76 (2H, m), 0.97 (3H, t, J=7.3 Hz).

2-Acetyl-4-propylpyridine:

The title compound was prepared from 4-propyl-2-pyridinecarbonitrileaccording to the procedure for preparing 2-acetyl-4-chloropyridinedescribed in Example 33.

¹H-NMR (CDCl₃) δ: 8.56 (1H, d, J=4.9 Hz), 7.88 (1H, s), 7.27-7.30 (1H,m), 2.72 (3H, s), 2.66 (2H, t, J=7.4 Hz), 1.62-1.76 (2H, m), 0.95 (3H,t, J=7.4 Hz).

2-Bromoacetyl-4-propylpyridine hydrobromide:

The title compound was prepared from 2-acetyl-4-propylpyridine accordingto the procedure for preparing 2-bromoacetyl-4-methylpyridinehydrobromide described in step 2 of Example 31.

¹H-NMR (DMSO-d₆) δ: 8.64 (1H, d, J=4.9 Hz), 7.90 (1H, d, J=1.0 Hz), 7.59(1H, dd, J=1.6, 4.9 Hz), 5.02 (2H, s), 2.70 (2H, t, J=7.4 Hz), 1.57-1.71(2H, m), 0.89 (3H, t, J=7.3 Hz).

Example 66[6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 from methyl2-[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 65).

m.p.: 189-191° C. IR (KBr) ν: 2964, 2928, 1711, 1645, 1595, 1533, 1281,1225, 1192, 799 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.28 (1H, br s), 8.73 (1H, d,J=5.1 Hz), 7.96 (1H, s), 7.73-7.81 (2H, m), 7.59 (1H, d, J=4.9 Hz),7.10-7.13 (1H, m), 4.08 (2H, s), 2.73 (2H, t, J=7.1 Hz), 1.63-1.72 (2H,m), 0.92 (3H, t, J=7.3 Hz).

Example 67Methyl[5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-4-propylpyridine hydrobromide(Preparation is described in Example 65).

¹H-NMR (CDCl₃) δ: 12.56 (1H, br s), 8.64 (1H, d, J=4.9 Hz), 8.18 (1H,s), 7.67 (1H, d, J=2.0 Hz), 7.45 (1H, d, J=8.7 Hz), 7.29-7.37 (2H, m),4.28 (2H, s), 3.74 (3H, s), 2.71 (2H, t, J=7.4 Hz), 1.80-1.66 (2H, m),0.97 (3H, t, J=7.3 Hz).

Example 68[5-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 67).

m.p.: 208-209° C. IR (KBr) ν: 3296, 2957, 1705, 1645, 1595, 1535, 1329,1273, 1204, 1057, 795 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.33 (1H, br s), 12.15(1H, br s), 8.73 (1H, d, J=4.9 Hz), 7.95 (1H, s), 7.86 (1H, s), 7.69(1H, d, J=8.7 Hz), 7.58-7.61 (1H, m), 7.31-7.35 (1H, m), 4.08 (2H, s),2.73 (2H, t, J=7.4 Hz), 1.64-1.72 (2H, m), 0.92 (3H, t, J=7.4 Hz).

Example 69Methyl[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 2-bromoacetyl-4-tert-butylpyridine*.

* 2-Bromoacetyl-4-tert-butylpyridine was prepared from2-acetyl-4-tert-butylpyridine (E. C. Constable et al., J. Am. Chem.Soc., 1997, 119, 5606) according to the procedure for preparing2-bromoacetyl-4-ethylpyridine described in Example 57.

¹H-NMR (CDCl₃) δ: 12.55 (1H, br s), 8.67 (1H, d, J=5.3 Hz), 8.39 (1H, d,J=2.1 Hz), 7.63 (1H, d, J=8.7 Hz), 7.53-7.55 (2H, m), 7.13 (1H, dd,J=1.8, 8.7 Hz), 4.31 (2H, s), 3.73 (3H, s), 1.38 (9H, s). ¹H-NMR (CDCl₃)δ: 8.58 (1H, d, J=4.8 Hz), 8.11 (1H, d, J=1.6 Hz), 7.51 (1H, dd, J=1.8,5.1 Hz), 4.86 (2H, s), 1.35 (9H, s).

Example 70[2-(4-tert-Butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetate(Example 69).

MS (EI) m/z: 370 (M⁺). m.p.: 203-205° C. IR (KBr) ν: 2966, 1699, 1647,1591, 1535, 1229 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.29 (1H, br s), 8.76 (1H,d, J=5.3 Hz), 8.10 (1H, d, J=2.0 Hz), 7.74-7.81 (3H, m), 7.12 (1H, dd,J=1.8, 8.6 Hz), 4.08 (2H, s), 1.36 (9H, s).

Example 71Methyl[2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-4-tert-butylpyridine (Preparationis described in Example 69).

¹H-NMR (CDCl₃) δ: 12.59 (1H, br s), 8.67 (1H, d, J=5.3 Hz), 8.38 (1H, d,J=2.0 Hz), 7.68 (1H, d, J=2.0 Hz), 7.54 (2H, dd, 2.0, 5.3 Hz), 7.45 (1H,d, J=8.9 Hz), 7.32 (1H, dd, J=2.0, 8.9 Hz), 4.29 (2H, s), 3.74 (3H, s),1.38 (9H, s).

Example 72[2-(4-tert-Butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetate(Example 71).

MS (EI) m/z: 370 (M⁺). m.p.: 209-211° C. IR (KBr) ν: 3269, 2968, 1746,1705, 1589, 1531, 1236, 1207, 1177, 1150, 1059, 737 cm⁻¹. ¹H-NMR(DMSO-d₆) δ: 12.33 (1H, br s), 8.76 (1H, d, J=5.3 Hz), 8.10 (1H, d,J=2.0 Hz), 7.86 (1H, d, J=2.0 Hz), 7.78 (1H, dd, J=2.0, 5.1 Hz), 7.69(1H, d, J=8.7 Hz), 7.33 (1H, dd, J=2.0, 8.7 Hz), 4.08 (2H, s), 1.36 (9H,s).

Example 73Methyl[6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 2-bromoacetyl-3-methylpyridinehydrobromide*.

* 2-Bromoacetyl-3-methylpyridine hydrobromide was prepared from2-acetyl-3-methylpyridine (T. A. Crabb et al., Org. Magn. Reson., 1982,20, 242) according to the procedure for preparing2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 ofExample 31.

¹H-NMR (CDCl₃) δ: 11.19 (1H, br s), 8.54 (1H, d, J=4.6 Hz), 7.65 (1H, d,J=7.7 Hz), 7.55 (1H, d, J=8.6 Hz), 7.33-7.38 (2H, m), 7.06 (1H, dd,J=1.8, 8.7 Hz), 4.15 (2H, s), 3.69 (3H, s), 2.59 (3H, s).

¹H-NMR (DMSO-d₆) δ: 8.56 (1H, d, J=3.6 Hz), 7.84 (1H, d, J=7.7 Hz),7.56-7.60 (1H, m), 5.01 (2H, s), 4.01 (3H, s).

Example 74[6-Chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 73).

MS (EI) m/z: 328 (M⁺). m.p.: 195-196° C. IR (KBr) ν: 3314, 1703, 1636,1526, 1418, 1396, 1231, 1196, 1150, 1109 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.14(1H, br s), 11.76 (1H, br s), 8.53 (1H, d, J=3.8 Hz), 7.85 (1H, d, J=7.9Hz), 7.74 (1H, d, J=8.6 Hz), 7.52-7.56 (2H, m), 7.10 (1H, dd, J=1.8, 8.6Hz), 3.66 (2H, s), 2.33 (3H, s).

Example 75Methyl[5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-3-methylpyridine hydrobromide(Preparation is described in Example 73).

¹H-NMR (CDCl₃) δ: 11.28 (1H, br s), 8.56 (1H, d, J=3.1 Hz), 7.61-7.69(2H, m), 7.23-7.41 (3H, m), 4.15 (2H, s), 3.70 (3H, s), 2.61 (3H, s).

Example 76[5-Chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 75).

m.p.: 209-211° C. (decomposed). IR (KBr) ν: 3379, 3271, 1728, 1649,1638, 1528, 1231, 1195, 1182, 1165, 1015 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.81(1H, br s), 8.53 (1H, d, J=4.4 Hz), 7.85 (1H, d, J=7.7 Hz), 7.80 (1H, d,J=2.0 Hz), 7.49-7.56 (2H, m), 7.31 (1H, dd, J=2.1, 8.7 Hz), 3.66 (2H,s), 2.33 (3H, s).

Example 77Methyl[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 2-bromoacetyl-6-methylpyridinehydrobromide (H. Erlenmeyer, J. Jenni, and B. Prijs, J. Med. Pharm.Chem., 1961, 3, 561-566).

¹H-NMR (CDCl₃) δ: 12.58 (1H, br s), 8.15 (1H, d, J=7.9 Hz), 7.83 (1H, t,J=7.7 Hz), 7.62 (1H, d, J=8.7 Hz), 7.51 (1H, d, J=1.8 Hz), 7.40 (1H, d,J=7.7 Hz), 7.13 (1H, dd, J=1.8, 8.7 Hz), 4.31 (2H, s), 3.72 (3H, s),2.76 (3H, s).

Example 78[6-Chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 77).

MS (EI) m/z: 328 (M⁺). m.p.: 230-231° C. IR (KBr) ν: 3273, 1697, 1643,1535, 1308, 1227, 1183, 1150, 797, 760, 671 cm⁻¹. ¹H-NMR (DMSO-d₆) δ:12.06 (1H, br s), 7.99 (1H, t, J=7.7 Hz), 7.87 (1H, d, J=7.6 Hz), 7.78(1H, d, J=8.9 Hz), 7.74 (1H, d, J=2.0 Hz), 7.59 (1H, d, J=7.6 Hz), 7.13(1H, dd, J=2.0, 8.7 Hz), 4.04 (2H, s), 2.69 (3H, s).

Example 79Methyl[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-5-methylpyridine (Preparation isdescribed in step 1 of Example 32).

¹H-NMR (CDCl₃) δ: 12.48 (1H, br s), 8.59 (1H, d, J=2.1 Hz), 8.24 (1H, d,J=8.1 Hz), 7.75 (1H, dd, J=2.1, 8.1 Hz), 7.67 (1H, d, J=2.0 Hz), 7.44(1H, d, J=8.7 Hz), 7.31 (1H, dd, J=2.0, 8.9 Hz), 4.29 (2H, s), 3.74 (3H,s), 2.48 (3H, s).

Example 80[5-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 79).

MS (EI) m/z: 328 (M⁺). m.p.: 247-248° C. IR (KBr) ν: 3288, 1699, 1638,1531, 1427, 1329, 1285, 1246, 1209, 1177, 1059, 1016, 800, 700 cm⁻¹.¹H-NMR (DMSO-d₆) δ: 12.30 (1H, br s), 12.15 (1H, br s), 8.68 (1H, br s),8.04 (1H, d, J=7.9 Hz), 7.93 (1H, br d, J=8.9 Hz), 7.84 (1H, br s), 7.69(1H, d, J=8.9 Hz), 7.33 (1H, dd, J=2.0, 8.9 Hz), 4.09 (2H, s), 2.46 (3H,s).

Example 81Methyl[6-chloro-2-[5-(trifuoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and2-bromoacetyl-5-(trifluoromethyl)pyridine*.

* 2-Bromoacetyl-5-(trifluoromethyl)pyridine was prepared from2-chloro-5-(trifluoromethyl)pyridine according to the procedure forpreparing 2-bromoacetyl-5-methylpyridine described in step 1 of Example32.

¹H-NMR (CDCl₃) δ: 11.97 (1H, br s), 9.07 (1H, br s), 8.48 (1H, d, J=8.4Hz), 8.23 (1H, dd, J=2.1, 8.4 Hz), 7.63 (1H, d, J=8.6 Hz), 7.52 (1H, d,J=1.8 Hz), 7.15 (1H, dd, J=1.8, 8.6 Hz), 4.31 (2H, s), 3.74 (3H, s).¹H-NMR (CDCl₃) δ: 8.96 (1H, br s), 8.23 (1H, br d, J=8.2 Hz), 8.13 (1H,dd, J=2.1, 8.1 Hz), 4.83 (2H, s).

Example 82[6-Chloro-2-[5-(trifuoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(5-trifluoromethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 81).

MS (EI) m/z: 382 (M⁺). m.p.: 228-229° C. IR (KBr) ν: 3325, 1707, 1636,1529, 1333, 1310, 1138, 1078, 1020 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.05 (1H,br s), 9.17 (1H, br s), 8.54 (1H, dd, J=2.0, 8.4 Hz), 8.24 (1H, d, J=8.2Hz), 7.82 (1H, d, J=8.6 Hz), 7.64 (1H, d, J=1.8 Hz), 7.14 (1H, dd,J=2.0, 8.7 Hz), 4.06 (2H, s).

Example 83Methyl[5-chloro-2-[5-(trifuoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-5-(trifluoromethyl)pyridine(Preparation is described in Example 81).

¹H-NMR (CDCl₃) δ: 12.01 (1H, br s), 9.05 (1H, br s), 8.45 (1H, d, J=8.2Hz), 8.21 (1H, dd, J=2.3, 8.4 Hz), 7.65 (1H, br s), 7.43 (1H, d, J=8.7Hz), 7.32 (1H, dd, J=2.0, 8.7 Hz), 4.27 (2H, s), 3.76 (3H, s).

Example 84[5-Chloro-2-[5-(trifuoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate(Example 83).

MS (EI) m/z: 382 (M⁺). m.p.: 230-231° C. IR (KBr) ν: 3300, 1720, 1701,1641, 1531, 1327, 1235, 1163, 1130, 1078, 1020, 864 cm⁻¹. ¹H-NMR(DMSO-d₆) δ: 12.09 (1H, br s), 9.17 (1H, br s), 8.54 (1H, dd, J=2.0, 8.2Hz), 8.23 (1H, d, J=8.2 Hz), 7.89 (1H, d, J=1.8 Hz), 7.62 (1H, d, J=8.9Hz), 7.36 (1H, dd, J=1.8, 8.9 Hz), 4.06 (2H, s).

Example 85Methyl[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-5-chloropyridine*.

* 2-Bromoacetyl-5-chloropyridine was prepared from2-bromo-5-chloropyridine (Case, J. Am. Chem. Soc., 1946, 68, 2574)according to the procedure for preparing 2-bromoacetyl-5-methylpyridinedescribed in step 1 of Example 32.

¹H-NMR (CDCl₃) δ: 12.01 (1H, br s), 8.72 (1H, d, J=2.5 Hz), 8.29 (1H, d,J=8.6 Hz), 7.93 (1H, dd, J=2.5, 8.6 Hz), 7.65 (1H, d, J=2.0 Hz), 7.43(1H, d, J=8.7 Hz), 7.31 (1H, dd, J=2.0, 8.7 Hz), 4.27 (2H, s), 3.75 (3H,s). ¹H-NMR (CDCl₃) δ: 8.63 (1H, dd, J=0.6, 2.5 Hz), 8.06 (1H, dd, J=0.6,8.4 Hz), 7.85 (1H, dd, J=2.3, 8.4 Hz), 4.79 (2H, s).

Example 86[5-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 85).

MS (EI) m/z: 348 (M⁺). m.p.: 259-260° C. IR (KBr) ν: 3314, 1703, 1632,1528, 1331, 1236, 1178, 1111, 1059, 1015, 806, 698 cm⁻¹. ¹H-NMR(DMSO-d₆) δ: 12.18 (1H, br s), 12.08 (1H, br s), 8.84 (1H, d, J=2.5 Hz),8.25 (1H, dd, J=2.5, 8.4 Hz), 8.10 (1H, d, J=8.6 Hz), 7.87 (1H, d, J=2.0Hz), 7.63 (1H, d, J=8.7 Hz), 7.34 (1H, dd, J=2.1, 8.9 Hz), 4.06 (2H, s).

Example 87Methyl[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 2-bromoacetyl-5-chloropyridine(Preparation is described in Example 85).

¹H-NMR (CDCl₃) δ: 11.98 (1H, br s), 8.74 (1H, dd, J=0.7 and 2.3 Hz),8.31 (1H, dd, J=0.7, 8.6 Hz), 7.94 (1H, dd, J=2.3, 8.4 Hz), 7.63 (1H, d,J=8.7 Hz), 7.52 (1H, d, J=1.6 Hz), 7.14 (1H, dd, J=1.8, 8.7 Hz), 4.30(2H, s), 3.73 (3H, s).

Example 88[6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 87).

MS (EI) m/z: 348 (M⁺). m.p.: 242-244° C. IR (KBr) ν: 3306, 1703, 1636,1529, 1308, 1234, 1151, 1109, 698 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.05 (1H,br s), 8.84 (1H, d, J=2.3 Hz), 8.26 (1H, dd, J=2.3, 8.4 Hz), 8.10 (1H,d, J=8.4 Hz), 7.80 (1H, d, J=8.7 Hz), 7.67 (1H, d, J=1.8 Hz), 7.13 (1H,dd, J=1.8, 8.7 Hz), 4.06 (2H, s).

Example 89Methyl[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-4-chloropyridine hydrobromide(Preparation is described in Example 33).

¹H-NMR (CDCl₃) δ: 12.20 (1H, br s), 8.67 (1H, d, J=5.3 Hz), 8.33 (1H, d,J=2.1 Hz), 7.66 (1H, d, J=2.0 Hz), 7.56 (1H, dd, J=2.1, 5.3 Hz), 7.43(1H, d, J=8.7 Hz), 7.32 (1H, dd, J=2.0, 8.9 Hz), 4.27 (2H, s), 3.75 (3H,s).

Example 90[5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 89).

MS (EI) m/z: 348 (M⁺). m.p.: 243-244° C. IR (KBr) ν: 3000, 1719, 1643,1528, 1242, 1202, 741 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.20 (1H, br s), 8.80(1H, d, J=5.3 Hz), 8.12 (1H, d, J=2.1 Hz), 7.90 (1H, dd, J=2.1, 5.4 Hz),7.66 (1H, d, J=8.9 Hz), 7.34 (1H, dd, J=2.0, 8.7 Hz), 4.06 (2H, s).

Example 91 Methyl[6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 3-bromoacetylpyridine hydrobromide(G. B. Barlin, L. P. Davies, S. J. Ireland, M. M. L. Ngu, Aust. J.Chem., 1989, 42, 1735).

¹H-NMR (CDCl₃) δ: 9.26 (1H, br s), 9.00 (1H, dd, J=0.8, 2.1 Hz), 8.80(1H, dd, J=1.6, 4.8 Hz), 8.10 (1H, dt, J=2.0, 2.0, 7.9 Hz), 7.58 (1H, d,J=8.7 Hz), 7.47 (1H, ddd, J=0.8, 4.9, 7.9 Hz), 7.37 (1H, d, J=1.8 Hz),7.16 (1H, dd, J=1.8, 8.6 Hz), 3.84 (2H, s), 3.65 (3H, s).

Example 92 [6-Chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetate (Example91).

MS (EI) m/z: 314 (M⁺). m.p.: 267-268° C. IR (KBr) ν: 3346, 1705, 1609,1566, 1528, 1433, 1418, 1327, 1267, 1215, 943, 761 cm⁻¹. ¹H-NMR(DMSO-d₆) δ: 12.28 (1H, br s), 11.86 (1H, br s), 8.90 (1H, br s), 8.85(1H, br d, J=4.9 Hz), 8.12 (1H, dt, J=2.0, 2.0, 7.9 Hz), 7.77 (1H, t,J=8.6 Hz), 7.62 (1H, dd, J=4.9, 8.0 Hz), 7.49 (1H, d, J=2.0 Hz), 7.15(1H, dd, J=1.6, 8.4 Hz), 3.85 (2H, s).

Example 93 Methyl[6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 4-bromoacetylpyridine hydrobromide(L. W. Deady, M. S. Stanborough, Aust. J. Chem., 1981, 34, 1295).

¹H-NMR (CDCl₃) δ: 9.21 (1H, br s), 8.82-8.79 (2H, m), 7.59-7.57 (2H, m),7.56 (1H, d, J=8.7 Hz), 7.33 (1H, d, J=1.8 Hz), 7.16 (1H, dd, J=1.8, 8.7Hz), 3.80 (2H, s), 3.65 (3H, s).

Example 94 [6-Chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetate (Example93).

MS (EI) m/z: 314 (M⁺). m.p.: 256-257° C. IR (KBr) ν: 3352, 1709, 1607,1528, 1431, 1329, 1259, 1202, 772, 687 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.82(1H, br s), 8.82 (2H, d, J=5.8 Hz), 7.77 (1H, d, J=8.6 Hz), 7.64-7.62(2H, m), 7.48 (1H, d, J=1.8Hz), 7.15 (1H, dd, J=2.0, 8.7 Hz), 3.83 (2H,s).

Example 95Methyl[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

Step 1.Methyl[6-chloro-2-[4-(tert-buthyldimethylsilyloxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and2-bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine*.

* 2-Bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine wasprepared as follows;

¹-NMR (CDCl₃) δ: 12.47 (1H, br s), 8.70 (1H, d, J=4.9 Hz), 8.21-8.22(1H, m), 7.55-7.58 (2H, m), 7.50-7.51 (1H, m), 7.10 (1H, dd, J=1.8, 8.7Hz), 4.83 (2H, s), 4.31 (2H, s), 3.72 (3H, s), 0.98 (9H, s), 0.15 (6H,s).

2-Acetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine:

The title compound was prepared from4-(tert-butyldimethylsilyloxymethyl)pyridinecarbonitrile (A. Hadri etal., J. Heterocycl. Chem., 1993, 30, 631) according to the procedure forpreparing 2-acetyl-4-chloropyridine described in Example 33.

¹H-NMR (CDCl₃) δ: 8.64 (1H, d, J=4.8 Hz), 7.96 (1H, s), 7.50 (1H, d,J=4.8 Hz), 4.80 (2H, s), 2.73 (3H, s), 0.96 (9H, s), 0.12 (6H, s).

2-Bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine:

To a solution of 2-acetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine(1.84 g, 6.932 mmol) in THF (50 ml) was added dropwise a solution oflithium bis(trimethylsilyl)amide (1M in THF, 8.3 ml, 8.3 mmol) at −78°C. After stirring for 1 h, chlorotriethylsilane (1.7 ml, 10.4 mmol) wasadded to the mixture at −78° C. The mixture was stirred at the sametemperature for 1 h, then allowed to warm to 0° C. After stirring for 1h, saturated aqueous ammonium chloride (50 ml) was added. The mixturewas extracted with diethyl ether (100 ml). The organic layer was washedwith water (50 ml), dried (MgSO₄) and concentrated. The residue wasdissolved in THF (20 ml), and then water (4 ml) and NBS were added at 0°C. After stirring for 1 h, the mixture was diluted with diethyl ether(200 ml), washed with water (50 ml) and dried (MgSO₄). Removal ofsolvent gave the crude product. Purification by flash columnchromatography eluting with ethyl acetate/hexane (1:20) to afford 0.74 g(31%) of the title compound as crystals.

¹H-NMR (CDCl₃) δ: 8.63 (1H, d, J=4.8 Hz), 8.02 (1H, q, J=0.8 Hz), 7.53(1H, dt, J=0.8, 4.9 Hz), 4.87 (2H, s), 4.81 (2H, s), 0.96 (9H, s), 0.13(3H, s).

Step 2.Methyl[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

To a solution ofmethyl[6-chloro-2-[4-(tert-buthyldimethylsilyloxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate(step 1, 171.5 mg, 0.3625 mmol) in THF (5 ml) was added a solution oftetrabutylammonium fluoride (1M in THF, 0.54 ml, 0.54 mmol) at roomtemperature. After stirring for 1 h, the mixture was concentrated. Theresidue was diluted with ethyl acetate (100 ml), washed with water (20ml×2) and dried (MgSO₄). Removal of solvent gave the crude product.Purification by flash column chromatography eluting with ethylacetate/hexane/dichloromethane (1:1:1) to afford 69.6 mg (54%) of thetitle compound as crystals.

¹H-NMR (CDCl₃) δ: 12.43 (1H, br s), 8.74 (1H, d, J=5.1 Hz), 8.29 (1H,s), 7.59-7.64 (2H, m), 7.52 (1H, d, J=1.5 Hz), 7.13 (1H, dd, J=1.6, 8.6Hz), 4.86 (2H, d, J=5.1 Hz), 4.31 (2H, s), 3.73 (3H, s).

Example 96[6-Chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate(Example 95).

MS (EI) m/z: 344 (M⁺). m.p.: 210-212° C. IR (KBr) ν: 3304, 1728, 1713,1622, 1583, 1526, 1194 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.31 (1H, br s), 8.78(1H, d, J=4.8 Hz), 8.08 (1H, s), 7.80 (1H, d, J=8.6 Hz), 7.74 (1H, d,J==1.8 Hz), 7.67 (1H, d, J=4.9 Hz), 7.12 (1H, dd, J=1.8, 8.7Hz), 4.69(2H, s), 4.09 (2H, s).

Example 97Methyl[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

Step 1.Methyl[5-chloro-2-[4-(tert-buthyldimethylsilyloxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate(Example 36, step 3) and2-bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine (Preparationis described in step 1 of Example 95).

¹H-NMR (CDCl₃) δ: 12.47 (1H, br s), 8.66 (1H, d, J=4.9 Hz), 8.18 (1H,s), 7.60-7.61 (1H, m), 7.54-7.57 (1H, m), 7.39 (1H, d, J=8.9 Hz), 7.25(1H, dd, J=2.0, 8.9 Hz), 4.82 (2H, s), 4.27 (2H, s), 3.74 (3H, s), 0.98(9H, s), 0.14 (6H, s).

Step 2.Methyl[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described instep 2 of Example 95 frommethyl[5-chloro-2-[4-(4-tert-buthyldimethylsilyloxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate(step 1).

¹H-NMR (CDCl₃) δ: 12.48 (1H, br s), 8.75 (1H, d, J=4.9 Hz), 8.31 (1H,s), 7.68 (1H, s), 7.60-7.62 (1H, m), 7.45 (1H, d, J=8.9 Hz), 7.32 (1H,dd, J=2.0, 8.9 Hz), 4.87 (2H, d, J=5.4 Hz), 4.28 (2H, s), 3.74 (3H, s).

Example 98[5-Chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate(Example 97).

MS (EI) m/z: 344 (M⁺). m.p.: 218-219° C. IR (KBr) ν: 3263, 1705, 1641,1595, 1528, 1327, 1198, 1061 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.34 (1H, br s),8.77 (1H, d, J=4.9 Hz), 8.08 (1H, s), 7.85 (1H, s), 7.66-7.71 (2H, m),7.33 (1H, dd, J=1.8, 8.9 Hz), 5.63 (1H, br s), 4.68 (2H, s), 4.09 (2H,s).

Example 99Methyl[5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-3,4-dimethylpyridinehydrobromide*.

* 2-Bromoacetyl-3,4-dimethylpyridine hydrobromide was prepared asfollows;

¹H-NMR (CDCl₃) δ: 12.20 (1H, br s), 8.67 (1H, d, J=5.3 Hz), 8.33 (1H, d,J=2.1 Hz), 7.66 (1H, d, J=2.0 Hz), 7.56 (1H, dd, J=2.1, 5.3 Hz), 7.43(1H, d, J=8.7 Hz), 7.32 (1H, dd, J=2.0, 8.9 Hz). 4.27 (2H, s), 3.75 (3H,s).

3,4-Dimethylpyridine-2-carbonitrile:

The title compound including 4,5-dimethylpyridine-2-carbonitrile in theratio of 5.5 to 1 was prepared from 3,4-dimethylpyridine-N-oxide(Abramovitch et al., J. Org. Chem., 1972, 37, 1690) according to theprocedure for preparing 4-chloro-2-pyridinecarbonitrile described inExample 33.

2-Acetyl-3,4-dimethylpyridine:

The title compound was prepared along with 2-acetyl-4,5-dimethylpyridinefrom 3,4-dimethylpyridine-2-carbonitrile including4,5-dimethylpyridine-2-carbonitrile in the ratio of 5.5 to 1 accordingto the procedure for preparing 2-acetyl-4-chloropyridine described inExample 33.

2-acetyl-3,4-dimethylpyridine: ¹H-NMR (CDCl₃) δ: 8.34 (1H, d, J=4.6 Hz),7.19 (1H, d, J=4.8 Hz), 2.69 (3H, s), 2.43 (3H, s), 2.34 (3H, s).

2-acetyl-4,5-dimethylpyridine: ¹H-NMR (CDCl₃) δ: 8.39 (1H, s), 7.83 (1H,s), 2.70 (3H, s), 2.33 (3H, s), 2.32 (3H, s).

2-Bromoacetyl-3,4-dimethylpyridine Hydrobromide:

The title compound was prepared from 2-acetyl-3,4-dimethylpyridineaccording to the method of H. McKennis, Jr., L. B. Turnbull, E, R.Bowman, and E. Tamaki (in J. Org. Chem., 1963, 23, 383-387).

¹H-NMR (DMSO-d₆) δ: 8.39 (1H, d, J=4.8 Hz), 7.46 (1H, d, J=4.8 Hz), 4.96(2H, s), 2.38 (3H, s), 2.35 (3H, s).

Example 100[5-Chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 99).

MS (EI) m/z: 342 (M⁺). m.p.: 236-237° C. IR (KBr) ν: 3395, 1710, 1641,1526, 1339, 1281, 1196, 1053, 1007 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.76 (1H,br s), 8.37 (1H, d, J=4.9 Hz), 7.79 (1H, d, J=2.0 Hz), 7.48 (1H, d,J=8.7 Hz), 7.41 (1H, d, J=4.9 Hz), 7.31 (1H, dd, J=2.0, 8.7 Hz), 3.56(2H, s), 2.35 (3H, s), 2.16 (3H, s).

Example 101Methyl[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-4,5-dimethylpyridine*.

* 2-Bromoacetyl-3,4-dimethylpyridine was prepared from2-acetyl-4,5-dimethylpyridine (Preparation is described in Example 99)according to the procedure for preparing 2-bromoacetyl-4-ethylpyridinedescribed in Example 57.

¹H-NMR (CDCl₃) δ: 12.59 (1H, br s), 8.47 (1H, s), 8.12 (1H, s), 7.67(1H, d, J=1.8 Hz), 7.44 (1H, d, J=9.4 Hz), 7.30 (1H, dd, J=2.0, 8.7 Hz),4.28 (2H, s), 3.73 (3H, s), 2.38 (6H, s). ¹H-NMR (CDCl₃) δ: 8.39 (1H,s), 7.87 (1H, s), 4.83 (2H, s), 2.35 (3H, s), 2.34 (3H, s).

Example 102[5-Chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 101).

MS (EI) m/z: 342 (M⁺). m.p.: 245-246° C. IR (KBr) ν: 3281, 1697, 1638,1589, 1535, 1254, 1232, 1188, 1060, 802 cm³¹ ¹. ¹H-NMR (DMSO-d₆) δ:12.34 (1H, br s), 12.15 (1H, br s), 8.57 (1H, s), 7.93 (1H, s), 7.84(1H, d, J=1.8 Hz), 7.69 (1H, d, J=8.7 Hz), 7.32 (1H, dd, J=2.0, 8.7 Hz),4.09 (2H, s), 2.39 (3H, s), 2.38 (3H, s).

Example 103Methyl[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 2-bromoacetyl-4,5-dimethylpyridine(Preparation is described in Example 99).

¹H-NMR (CDCl₃) δ: 12.55 (1H, br s), 8.47 (1H, s), 8.12 (1H, s), 7.62(1H, d, J=8.6 Hz), 7.52 (1H, d, J=1.8 Hz), 7.13 (1H, dd, J=1.8, 8.6 Hz),4.31 (2H, s), 3.72 (3H, s), 2.39 (6H, s).

Example 104 [6-Chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 103).

MS (EI) m/z: 342 (M⁺). m.p.: 226-228° C. IR (KBr) ν: 3275, 1697, 1638,1537,1258, 1188, 799 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.30 (1H, br s), 8.57(1H, s), 7.94 (1H, s), 7.78 (1H, d, J=8.7 Hz), 7.74 (1H, d, J=1.8 Hz),7.11 (1H, dd, J=2.0, 8.6 Hz), 4.09 (2H, s), 2.39 (3H, s), 2.38 (3H, s).

Example 105Methyl[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 2-bromoacetyl-4-methoxypyridinehydrobromide*.

* 2-Bromoacetyl-4-methoxypyridine hydrobromide was prepared from2-acetyl-4-methoxypyridine (B. Case et al., J. Org. Chem., 1961, 26,4415) according to the procedure for preparing2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 ofExample 31.

¹H-NMR (CDCl₃) δ: 12.61 (1H, br s), 8.57 (1H, d, J=5.9 Hz), 7.89 (1H, d,J=2.6 Hz), 7.63 (1H, d, J=8.6 Hz), 7.52 (1H, d, J=1.8 Hz), 7.13 (2H, dd,J=1.8, 8.7 Hz), 7.04 (1H, dd, J=2.6, 5.8 Hz), 4.30 (2H, s), 3.96 (3H,s), 3.73 (3H, s). ¹H-NMR (DMSO-d₆) δ: 8.59-8.62 (1H, m), 7.63-7.65 (1H,m), 7.33-7.37 (1H, m), 5.03 (2H, s), 3.96 (3H, s).

Example 106[6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 105).

MS (EI) m/z: 344 (M⁺). m.p.: 213° C.(decomposed). IR (KBr) ν: 3200,1709, 1645, 1589, 1533, 1225, 1207 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.35 (1H,br s), 12.18 (1H, br s), 8.66 (1H, d, J=5.6 Hz), 7.80 (1H, d, J=8.9 Hz),7.74 (1H, d, J=1.8 Hz), 7.63 (1H, d, J=2.6 Hz), 7.31 (1H, dd, J=2.9, 5.1Hz), 7.12 (1H, dd, J=1.3, 8.7 Hz), 4.09 (2H, s), 3.96 (3H, s).

Example 107Methyl[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-4-methoxypyridine hydrobromide(Preparation is described in Example 105).

¹H-NMR (CDCl₃) δ: 12.65 (1H, br s), 8.57 (1H, d, J=5.8 Hz), 7.88 (1H, d,J=2.5 Hz), 7.68 (1H, d, J=2.0 Hz), 7.45 (1H, dd, J=0.5, 8.7 Hz), 7.32(1H, dd, J=1.8, 8.7 Hz), 7.05 (1H, dd, J=2.8, 5.8 Hz), 4.28 (2H, s),3.96 (3H, s), 3.74 (3H, s).

Example 108[5-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 107).

m.p.: 228° C. (decomposed). IR (KBr) ν: 3230, 1707, 1647, 1595, 1566,1533, 1477, 1331, 1300, 1219, 1180, 1038, 1013 cm⁻¹. ¹H-NMR (DMSO-d₆) δ:12.39 (1H, br s), 12.16 (1H, br s), 8.66 (1H, d, J=5.8 Hz), 7.86 (1H, d,J=1.5 Hz), 7.70 (1H, d, J=8.7 Hz), 7.63 (1H, d, J=2.5 Hz), 7.29-7.35(2H, m), 4.09 (2H, s), 3.96 (3H, s).

Example 109Methyl[6-chloro-2-(3.5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 2-bromoacetyl-3,5-dimethylpyridinehydrobromide*.

* 2-Bromoacetyl-3,5-dimethylpyridine hydrobromide was prepared asfollows;

¹H-NMR (CDCl₃) δ: 11.43 (1H, br s), 8.43 (1H, s), 7.60 (1H, d, J=8.7Hz), 7.51 (1H, s), 7.45 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=1.8, 8.7 Hz),4.22 (2H, s), 3.69 (3H, s), 2.62 (3H, s), 2.43 (3H, s).

2-Acetyl-3,5-dimethylpyridine:

The title compound was prepared from 3,5-dimethylpyridinecarbonitrile(K. Takahashi et al., J. Heterocycl. Chem., 1978, 15, 893) according tothe procedure for preparing 2-acetyl-4-chloropyridine described inExample 33. ¹H-NMR (CDCl₃) δ: 8.32 (1H, s), 7.37 (1H, s), 2.69 (3H, s),2.56 (3H, s), 2.36 (3H, s). 2-Bromoacetyl-3,5-dimethylpyridinehydrobromide:

The title compound was prepared from 2-acetyl-3,5-dimethylpyridineaccording to the method of H. McKennis, Jr., L. B. Tumbull, E, R.Bowman, and E. Tamaki (in J. Org. Chem., 1963, 23, 383-387).

¹H-NMR (DMSO-d₆) δ: 8.43 (1H, s), 7.69 (1H, s), 5.00 (2H, s), 2.52 (3H,s), 2.39 (3H, s).

Example 110[6-Chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 109).

MS (EI) m/z: 342 (M⁺). m.p.: 199-200° C. IR (KBr) ν: 3279, 1705, 1639,1526, 1238, 1177, 827, 797 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.12 (1H, br s),11.72 (1H, br s), 8.38 (1H, s), 7.74 (1H, d, J=8.6 Hz), 7.68 (1H, s),7.52 (1H, d, J=2.0 Hz), 7.10 (1H, dd, J=1.8, 8.6 Hz), 3.72 (2H, s), 2.38(3H, s), 2.33 (3H, s).

Example 111Methyl[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-4-ethyl-3-fluoropyridine*.

* 2-Bromoacetyl-4-ethyl-3-fluoropyridine was prepared as follows;

¹H-NMR (CDCl₃) δ: 11.29 (1H, br s), 8.45 (1H, d, J=4.8 Hz), 7.64 (1H, d,J=1.8 Hz), 7.44 (1H, t, J=4.8 Hz), 7.38 (1H, d, J=8.9 Hz), 7.29 (1H, dd,J=2.0, 8.7 Hz), 4.21 (2H, s), 3.72 (3H, s), 2.81 (2H, q, J=7.6 Hz), 1.31(3H, t, J=7.6 Hz).

4-Ethyl-3-fluoropyridine-N-oxide:

To a mixture of 4-ethyl-3-fluoropyridine (R. P. Dikinson et al., Bioorg.Med. Chem. Lett., 1996, 6, 2031, 28.51 g, 205.9 mmol) and 30% hydrogenperoxide (30 ml) in acetic acid (300 ml) was heated at refluxtemperature for 3 h. After cooling to room temperature, the resultingmixture was concentrated. The residue was diluted in dichloromethane(300 ml) and dried (MgSO₄). Removal of solvent gave 32.30 g (100%) ofthe title compound as an oil.

¹H-NMR (DMSO-d₆) δ: 8.43-8.46 (1H, m), 8.08 (1H, d, J=6.1 Hz), 7.38 (1H,dd, J=6.6, 9.7 Hz), 2.61 (2H, q, J=7.6 Hz), 1.17 (3H, t, J=7.6 Hz).

4-Ethyl-3-fluoro-2-pyridinecarbonitrile:

The title compound was prepared from 4-ethyl-3-fluoropyridine-N-oxideaccording to the procedure for preparing 4-chloro-2-pyridinecarbonitriledescribed in Example 33.

¹H-NMR (CDCl₃) δ: 8.42 (1H, d. J=4.8 Hz), 7.43 (1H, t, J=5.1 Hz), 2.78(2H, q, J=7.6 Hz), 1.30 (3H, t, J=7.6 Hz).

2-Acetyl-4-ethyl-3-fluoropyridine:

The title compound was prepared from4-ethyl-3-fluoro-2-pyridinecarbonitrile according to the procedure forpreparing 2-acetyl-4-chloropyridine described in Example 33.

¹H-NMR (CDCl₃) δ: 8.376 (1H, d, J=4.6 Hz), 7.36 (1H, t, J=4.8 Hz), 2.76(2H, q, J=7.6 Hz), 2.71 (3H, s), 1.28 (3H, t, J=7.6 Hz).

2-Bromoacetyl-4-ethyl-3-fluoropyridine:

The title compound was prepared from 2-acetyl-4-ethyl-3-fluoropyridineaccording to the procedure for preparing 2-bromoacetyl-4-ethylpyridinedescribed in Example 57.

¹H-NMR (CDCl₃) δ: 8.38 (1H, d, J=4.6 Hz), 7.43 (1H, d, J=4.6 Hz), 4.75(2H, s), 2.78 (2H, q, J=7.6 Hz), 1.29 (3H, t, J=7.6 Hz).

Example 112[5-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticAcid

A stirred solution ofmethyl[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 111, 391.2 mg, 1.044 mmol) in acetic acid (12 ml) and 2Naqueous HCl (4 ml) was heated at reflux temperature for 24 h. Aftercooling to room temperature, the resulting mixture was concentrated. Theresidue was diluted in THF (100 ml), dried (MgSO₄) and concentrated. Thecrude product was purified by recrystallization to afford 349.2 mg (93%)of the title compound.

MS (EI) m/z: 361 (M⁺). m.p.: 208° C. IR (KBr) ν: 3217, 1720, 1632, 1516,1429, 1234, 1180, 1057 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.78 (1H, br s), 8.35(1H, d, J=4.8 Hz), 7.73 (1H, d, J=2.0 Hz), 7.56 (1H, t, J=5.1 Hz), 7.39(1H, d, J=8.9 Hz), 7.22 (1H, dd, J=2.0, 8.9 Hz), 3.65 (2H, s), 2.65 (2H,q, J=7.6 Hz), 1.14 (3H, t, J=7.6 Hz).

Example 113Methyl[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate(step 1 of Example 8, Method A).

¹H-NMR (CDCl₃) δ: 11.23 (1H, br s), 8.46 (1H, d, J=4.8 Hz), 7.60 (1H, d,J=9.2 Hz), 7.42-7.46 (2H, m), 7.10-7.14 (1H, m), 4.23 (2H, s), 3.71 (3H,s), 2.81 (2H, q, J=7.7 Hz), 1.31 (3H, t, J=7.7 Hz).

Example 114[6-Chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 113).

m.p.: 165° C. IR (KBr) ν: 3300, 2974, 1705, 1645, 1529, 1339, 1178 cm⁻¹.¹H-NMR (DMSO-d₆) δ: 11.65 (1H, br s), 8.32 (1H, d, J=4.6 Hz), 7.73 (1H,d, J=8.9 Hz), 7.47-7.52 (2H, m), 7.10 (1H, dd, J=1.8, 8.6 Hz), 3.89 (2H,q, J=6.9 Hz), 3.70 (2H, s), 2.72 (2H, q, J=7.6 Hz), 1.13-1.26 (6H, m).

Example 115Methyl[6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and2-bromoacetyl-3-chloro-4-ethylpyridine hydrobromide*.

* 2-Bromoacetyl-3-chloro-4-ethylpyridine hydrobromide was prepared asfollows;

¹H-NMR (CDCl₃) δ: 10.05 (1H, br s), 8.47 (1H, d, J=4.9 Hz), 7.53 (1H, d,J=8.7 Hz), 7.32-7.34 (2H, m), 7.05 (IR, dd, J=1.8, 8.7 Hz), 3.79 (2H,s), 3.61 (3H, s), 2.83 (2H, q, J=7.6 Hz), 1.28 (3H, t, J=7.6 Hz).

3-Chloro-4-ethylpyridine-N-oxide:

The title compound was prepared from 3-chloro-4-ethylpyridine (F.Marsais et al., J. Organomet. Chem., 1981, 216, 139) according to theprocedure for preparing 4-ethyl-3-fluoropyridine-N-oxide described inExample 111.

¹H-NMR (DMSO-d₆) δ: 8.46 (1H, d, J=1.8 Hz), 8.16 (1H, d, J=6.6 Hz), 7.40(1H, dd, J=1.8, 6.6 Hz), 2.67 (2H, q, J=7.6 Hz), 1.14-1.19 (3H, m).

3-Chloro-4-ethyl-2-pyridinecarbonitrile:

The title compound was prepared from 3-chloro-4-ethylpyridine-N-oxideaccording to the procedure for preparing 4-chloro-2-pyridinecarbonitriledescribed in Example 33.

¹ ¹H-NMR (CDCl₃) δ: 8.50 (1H, d, J=4.9 Hz), 7.41 (1H, t, J=4.9 Hz), 2.84(2H, q, J=7.4 Hz), 1.30 (3H, t, J=7.6 Hz).

2-Acetyl-3-chloro-4-ethylpyridine:

The title compound was prepared from3-chloro-4-ethyl-2-pyridinecarbonitrile according to the procedure forpreparing 2-acetyl-4-chloropyridine described in Example 33.

¹H-NMR (CDCl₃) δ: 8.41 (1H, d, J=4.8 Hz), 7.29 (1H, d, J=4.8 Hz), 2.83(2H, q, J=7.6 Hz), 2.67 (3H, s), 1.27 (3H, t, J=7.6 Hz).

2-Bromoacetyl-3-chloro-4-ethylpyridine hydrobromide:

The title compound was prepared from 2-acetyl-3-chloro-4-ethylpyridineaccording to the procedure for preparing 2-bromo-4-methylpyridinehydrobromide described in step 2 of Example 31.

¹H-NMR (DMSO-d₆) δ: 8.55 (1H, d, J=4.9 Hz), 7.66 (1H, d, J=4.8 Hz), 4.93(2H, s), 2.82 (2H, q, J=7.3 Hz), 1.21 (3H, t, J=7.4 Hz).

Example 116[6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 115).

m.p.: 158° C. IR (KBr) ν: 3335, 1730, 1630, 1529, 1325, 1200 cm⁻¹.¹H-NMR (DMSO-d₆) δ: 11.83 (1H, br s), 8.54 (1H, d, J=4.8 Hz), 7.75 (1H,d, J=8.7 Hz), 7.63 (1H, d, J=4.9 Hz), 7.46 (1H, s), 7.12 (1H, dd, J=1.8,8.7 Hz), 3.57 (2H, s), 2.82 (2H, q, J=7.4 Hz), 1.25 (3H, t, J=7.4 Hz).

Example 117Methyl[5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-3-chloro-4-ethylpyridinehydrobromide (Preparation is described in Example 115).

¹H-NMR (CDCl₃) δ: 9.87 (1H, br s), 8.50 (1H, d, J=4.9 Hz), 7.64 (1H, s),7.29-7.40 (3H, m), 3.86 (2H, s), 3.63 (3H, s), 2.88 (2H, q, J=7.6 Hz),1.32 (3H, t, J=7.6 Hz).

Example 118[5-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 117).

m.p.: 220° C. IR (KBr) ν: 3341, 1695, 1626, 1533, 1458, 1429, 1229 cm⁻¹.¹H-NMR (DMSO-d₆) δ: 11.88 (1H, br s), 8.54 (1H, d, J=4.9 Hz), 7.82 (1H,s), 7.63 (1H, d, J=4.9 Hz), 7.46 (1H, d, J=8.9 Hz), 7.34 (1H, dd, J=2.0,8.9 Hz), 3.60 (2H, s), 2.82 (2H, q, J=7.4 Hz), 1.25 (3H, t, J=7.4 Hz).

Example 119Methyl[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-4,6-dimethylpyridine*.

* 2-Bromoacetyl-3,4-dimethylpyridine was prepared from2-acetyl-4,6-dimethylpyridine (Sundberg et al., J. Am. Chem. Soc., 1969,91, 658) according to the procedure for preparing2-bromoacetyl-4-ethylpyridine described in Example 57.

¹H-NMR (CDCl₃) δ: 12.73 (1H br s), 7.98 (1H, s), 7.67 (1H, br s), 7.42(1H, d, J=8.9 Hz), 7.30 (1H, dd, J=1.8 and 8.7 Hz), 7.22 (1H, s), 4.27(2H, s), 3.73 (3H, s), 2.70 (3H, s), 2.43 (3H, s). ¹H-NMR (CDCl₃) δ:7.72 (1H, s), 7.19 (1H, s), 5.13 (2H, s), 2.55 (3H, s), 2.38 (3H, s).

Example 120[5-Chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 119).

MS (EI) m/z: 342 (M⁺). m.p.: 233-235° C. IR (KBr) ν: 3288, 2919, 1742,1630, 1599, 1529, 1333, 1232, 1180, 1067, 772 cm⁻¹. ¹H-NMR (DMSO-d₆) δ:11.99 (1H, br s), 7.69 (1H, s), 7.57 (1H, s), 7.52 (1H, d, J=8.9 Hz),7.28 (1H, s), 7.18 (1H, dd, J=2.1, 8.9 Hz), 3.87 (2H, s), 2.49 (3H, s),2.27 (3H, s).

Example 121Methyl[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 2-bromoacetyl-4,6-dimethylpyridine(Preparation is described in Example 119).

¹H-NMR (CDCl₃) δ: 12.69 (1H, br s), 7.98 (1H, s), 7.62 (1H, d, J=8.7Hz), 7.50 (1H, d, J=0.7 Hz), 7.22 (1H, s), 7.12 (1H, dd, J=1.6, 8.6 Hz),4.30 (2H, s), 3.72 (3H, s), 2.70 (3H, s), 2.43 (3H, s).

Example 122[6-Chloro-2-(4,6-dimethylpyridine-2-carbonyl-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 121).

MS (EI) m/z: 342 (M⁺). m.p.: 219-220° C. IR (KBr) ν: 3300,1701, 1639,1603, 1535, 1225, 1180 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.95 (1H, br s), 7.62(1H, d, J=8.7 Hz), 7.58 (1H, d, J=1.3 Hz), 7.56 (1H, s), 7.27 (1H, s),6.96 (1H, dd, J=2.0, 8.7 Hz), 3.87 (2H, s), 2.49 (3H, s), 2.26 (3H, s).

Example 123Methyl[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

Step 1. Methyl trans-4,5-Dichloro-2-nitrocinnamate

The title compound was prepared according to the procedure described instep 1 of Example 36 from 4,5-dichloro-2-nitrobenzaldehyde (J. Kennethet al., J. Med. Chem., 1968, 11, 946).

¹H-NMR (CDCl₃) δ: 8.20 (1H, s), 8.04 (1H, d, J=15.8 Hz), 7.72 (1H, s),6.36 (1H, d, J=15.8 Hz).

Step 2. Methyl trans-2-Amino-4,5-dichlorocinnamate

The title compound was prepared according to the procedure described instep 2 of Example 36 from methyl trans-4,5-dichloro-2-nitrocinnamate(step 1).

¹H-NMR (CDCl₃) δ: 7.65 (1H, d, J=15.8 Hz), 7.42 (1H, s), 7.26 (1H, s),6.81 (1H, s), 6.28 (1H, d, J=15.8 Hz).

Step 3. Methyl trans-4,5-Dichloro-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-2-amino-4,5-dichlorocinnamate (step 2).

¹H-NMR (CDCl₃) δ: 7.80-7.70 (2H, m), 7.60-7.40 (6H, m), 7.02 (1H, br s),6.13 (1H, d, J=16.1 Hz), 3.79 (3H, s).

Step 4.Methyl[(5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-4,5-dichloro-2-(phenylsulfonylamino)cinnamate (step 3) and2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described instep 2 of Example 31).

¹H-NMR (DMSO-d₆) δ: 12.45 (1H, br s), 8.69 (1H, d, J=5.1 Hz). 8.14 (1H,s), 8.00-7.93 (2H, m), 7.59 (1H, d, J=4.3 Hz), 4.16 (2H, s), 3.59 (3H,s), 3.32 (3H, s).

Example 124[5,6-Dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The titled compound was prepared according to the procedure described inExample 58 frommethyl[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 123).

m.p.: 220-224° C. ¹H-NMR (DMSO-d₆) δ: 12.41 (1H, s), 12.20 (1H, br s),8.69 (1H, d, J=5.1 Hz), 8.11 (1H, s), 7.96-7.58 (2H, m), 7.58 (1H, d,J=4.8 Hz), 4.08 (2H, s), 2.47 (3H, s).

Example 125Methyl[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

Step 1. Methyl trans-2-Amino-5-methylcinnamate

The title compound was prepared according to the procedure described instep 2 of Example 36 from methyl trans-5-methyl-2-nitrocinnamate (C.Venkatasubban, J. Annamalai Univ., 1933, 2, 227).

¹H-NMR (CDCl₃) δ: 7.82 (1H, d, J=15.8 Hz), 7.20-7.19 (1H, m), 7.01-6.98(1H, m), 6.63 (1H, d, J=8.2 Hz), 6.35 (1H, d, J=15.8 Hz), 3.83 (2H, m),3.80 (3H, s), 2.24 (3H, s).

Step 2. Methyl trans-5-Methyl-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-2-amino-5-methylcinnamate (step 1).

¹H-NMR (CDCl₃) δ: 7.70-7.67 (2H, m), 7.55-7.38 (4H, m), 7.26-7.14 (3H,m), 6.55 (1H, br s), 6.14(1H, d, J=16.0 Hz), 3.77(3H, s), 2.33 (3H, s).

Step 3.Methyl[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetateThe title compound was prepared according to the procedure described inExample 57 from methyl trans-5-methyl-2-(phenylsulfonylamino)cinnamate(step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation isdescribed in step 2 of Example 31).

¹H-NMR (CDCl₃) δ: 12.32 (1H, br s), 8.61 (1H, d, J=5.0 Hz), 8.17 (1H,s), 7.46 (1H, s), 7.40 (1H, d, J=8.6 Hz), 7.33-7.32 (1H, m), 7.22-7.19(1H, m), 4.31 (2H, s), 3.72 (3H, s), 2.46 (6H, m).

Example 126[5-Methyl-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 125).

m.p.: 220-226° C. IR (KBr) ν: 3736, 3649, 1697, 1533, 1508, 1398, 1194,802 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.08 (1H, br s), 8.69 (1H, d, J=4.8 Hz),7.94 (1H, s), 7.56-7.49 (3H, m), 7.17 (1H, dd, J=8.4 Hz), 4.05 (2H, s),2.46 (3H, s), 2.40 (3H, s).

Example 127Methyl[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

Step 1. Methyl trans-5-Fluoro-2-nitrocinnamate

The title compound was prepared according to the procedure described instep 1 of Example 36 from 5-fluoro-2-nitrobenzaldehyde.

¹H-NMR (CDCl₃) δ: 8.17-8.10 (2H, m), 7.32-7.19 (2H, m), 6.36 (1H, d,J=15.8 Hz), 3.84 (3H, s).

Step 2. Methyl trans-5-Fluoro-2-aminocinnamate

The title compound was prepared according to the procedure described instep 2 of Example 36 from methyl trans-5-fluoro-2-nitrocinnamate (step1).

¹H-NMR (CDCl₃) δ: 7.77 (1H, dd, J=15.8, 1.5 Hz), 7.10-7.06 (1H, m),6.94-6.87 (1H, m), 6.68-6.63 (1H, m), 6.33 (1H, d, J=15.8 Hz), 3.85 (2H,m), 3.81 (3H, s).

Step 3. Methyl trans-5-Fluoro-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-5-fluoro-2-aminocinnamate (step 2).

¹H-NMR (CDCl₃) δ: 7.68-7.65 (2H, m), 7.55-7.49 (2H, m), 7.44-7.33 (3H,m), 7.18-7.13 (1H, m), 7.10-7.04 (1H, m), 6.10 (1H, d, J=15.8 Hz), 3.78(3H, s).

Step 4.Methyl[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-fluoro-2-(phenylsulfonylamino)cinnamate(step 3).

¹H-NMR (CDCl₃) δ: 12.46 (1H, br s), 8.58-8.56 (1H, m), 8.12 (1H, s),7.43-7.39 (1H, m), 7.33-7.26 (2H, m), 7.14-7.06 (1H, m), 4.26 (2H, s),3.74 (3H, s), 2.45 (3H, s).

Example 128[5-Fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 127).

m.p.: 223° C. (decomposed). IR (KBr) ν: 1705, 1643, 1570, 1277, 1227,1204, 1186 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.28 (1H, br s), 8.70 (1H, d,J=4.9 Hz), 7.95 (1H, s), 7.71-7.66 (1H, m), 7.58-7.52 (2H, m), 7.25-7.17(1H, m), 4.06 (2H, s), 2.47 (3H, s).

Example 129Methyl[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

Step 1. Methyl trans-5-Methoxy-2-nitrocinnamate

The title compound was prepared according to the procedure described instep 1 of Example 36 from 5-methoxy-2-nitrobenzaldehyde.

¹H-NMR (CDCl₃) δ: 8.21 (1H, d, J=15.8 Hz), 8.16-8.12 (1H, m), 7.00-6.96(2H, m), 6.30 (1H, d, J=15.8 Hz), 3.93 (3H, s), 3.83 (3H, s).

Step 2. Methyl trans-5-Methoxy-2-aminocinnamate

The title compound was prepared according to the procedure described instep 2 of Example 36 from methyl trans-5-methoxy-2-nitrocinnamate (step1).

¹H-NMR (CDCl₃) δ: 7.83 (1H, d, J=15.8 Hz), 6.92-6.91 (1H, m), 6.82 (1H,dd, J=8.7, 2.8 Hz), 6.66 (1H, d, J=8.7 Hz), 6.35 (1H, d, J=15.8 Hz),3.80 (3H, s), 3.76 (3H, s).

Step 3. Methyl trans-5-Methoxy-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-5-methoxy-2-aminocinnamate (step 2).

¹ ¹H-NMR (CDCl₃) δ: 7.67-7.64 (2H, m), 7.54-7.37 (4H, m), 7.24 (1H, d,J=8.7 Hz), 6.95 (1H, d, J=2.8 Hz), 6.89 (1H, dd, J=8.7, 2.8 Hz), 6.82(1H, br s), 6.10 (1H, d, J=15.8 Hz), 3.81 (3H, s), 3.77 (3H, s).

Step 4.Methyl[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-methoxy-2-(phenylsulfonylamino)cinnamate(step 3).

¹H-NMR (CDCl₃) δ: 12.38 (1H, br s), 8.61 (1H, d, J=4.9 Hz), 8.17 (1H,s), 7.40 (1H, d, J=8.7 Hz), 7.34-7.32 (1H, m), 7.08-7.03 (2H, m), 4.31(2H, s), 3.88 (3H, s), 3.73 (3H, s), 2.47 (3H, s).

Example 130[5-Methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The titled compound was prepared according to the procedure described inExample 58 frommethyl[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 129).

m.p.: 235° C. (decomposed). IR (KBr) ν: 1701, 1638, 1595, 1528, 1448,1423, 1340, 1279, 1263, 1234, 1223, 1192, 1111 cm⁻¹. ¹H-NMR (DMSO-d₆) δ:12.11 (1H, br s), 8.69 (1H, d, J=4.9 Hz), 7.95 (1H, s), 7.58-7.55 (2H,m), 7.18 (1H, m), 7.02-6.98 (1H, m), 4.07 (2H, s), 3.79 (3H, s), 2.46(3H, s).

Example 131Methyl[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

Step 1. Methyl trans-(4-Methoxy-2-nitro)cinnamate

A mixture of 4-bromo-3-nitroanisole (4.177 g, 18.0 mmol), methylacrylate (3.24 ml, 36.0 ml), palladium(II) acetate (606.1 mg, 2.7 mmol),triphenylphosphine (1.416 g, 5.4 mmol), triethylamine (3.76 ml, 27.0mmol) in DMF (45.0 ml) was stirred at 130° C. for 4 h. After cooling toambient temperature, the mixture was concentrated. To the residue wasadded water (30 ml), and then the mixture was extracted with ethylacetate-toluene (3:1, 40 ml). The aqueous layer was further extractedwith ethyl acetate (2×30 ml ). The combined organic layers were dried(MgSO₄) and concentrated to afford 6.42g (quant.) of the title compoundas an brown oil.

¹H-NMR (CDCl₃) δ: 8.07-6.97 (4H, m), 6.31 (1H, d, 15.8 Hz), 3.90 (3H,s), 3.82 (3H, s).

Step 2. Methyl trans-2-Amino-4-methoxycinnamate

The title compound was prepared according to the procedure described instep 2 of Example 36 from methyl trans-(4-methoxy-2-nitro)cinnamate(step 1).

¹H-NMR (CDCl₃) δ: 7.80-6.21 (5H, m), 4.03 (2H, br s), 3.79 (6H, s).

Step 3. Methyl trans-4-Methoxy-2-(p-toluenesulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-4-methoxy-2-aminocinnamate (step 2).

¹H-NMR (CDCl₃) δ: 7.62-6.73 (9H, m), 6.07 (1H, d, 15.8 Hz), 3.80 (3H,s), 3.77 (3H, s), 2.37 (3H, s).

Step 4.Methyl[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-4-methoxy-2-(p-toluenesulfonylamino)cinnamate (step 3) and2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described instep 2 of Example 31).

¹H-NMR (CDCl₃) δ: 12.32 (1H, br s), 8.61 (1H, d, 4.94 Hz), 8.19-7.55(2H, m), 7.34-6.82 (311, m), 4.31 (2H, s), 3.89 (3H, s), 3.72 (3H, s),2.47 (3H, s).

Example 132[6-Methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 131).

m.p.: 204° C. IR (KBr) ν: 3198, 1709, 1630, 1593, 1531, 1460, 1423,1334, 1275, 1213, 1161, 1136, 1039, 1001 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.11(1H, br s), 8.68 (1H, d, 4.94 Hz), 7.94 (11H, m), 7.62 (1H, d, 8.88 Hz),7.56-7.52 (1H, m), 7.14 (1H, d, 2.30 Hz), 6.76 (1H, dd, 8,88 Hz, 2.30Hz), 4.05 (2H, s), 3.82 (3H, s), 2.47 (3H, s).

Example 133Methyl[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

Step 1. Methyl trans-5-Ethyl-2-aminocinnamate

A mixture of 2-bromo-4-ethylaniline (1.0 g, 5.10 mmol), methyl acrylate(1.15 ml, 12.74 mmol), palladium(II) acetate (137 mg, 0.61 mmol),tri-o-tolylphosphine (745 mg, 2.45 mmol), and triethylamine (2.5 ml) inacetonitrile (10 ml) was heated at 110° C. After stirring for 2 h,methyl acrylate (0.6 ml, 6.37 mmol), palladium(II) acetate (69 mg, 0.30mmol), tri-o-tolylphosphine (372 mg, 1.22 mmol), triethylamine (1.3 ml)were added and the mixture was stirred at 110° C. for 7 h. The solventwas removed and the residue was diluted with ethyl acetate (100 ml),washed with water (100 ml), dried (MgSO₄) and concentrated. The residuewas purified by flash column chromatography eluting with ethylacetate/hexane (1:5/1:4) to afford 793 mg (75.8%) of the title compoundas yellow solids.

¹H-NMR (CDCl₃) δ: 7.83 (1H, d, J=15.8 Hz), 7.21 (1H, m), 7.04-7.01 (1H,m), 6.64 (1H, d, J=8.2 Hz), 6.36 (1H, d, J=15.8 Hz), 3.87 (2H, m), 3.80(3H, s), 2.51 (2H, q, J=7.6 Hz), 1.19 (3H, t, J=7.6 Hz).

Step 2. Methyl trans-5-Ethyl-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-5-ethyl-2-aminocinnamate (step 1).

¹H-NMR (CDCl₃) δ: 7.70-7.48 (4H, m), 7.42-7.36 (2H, m), 7.29-7.26 (2H,m), 7.20-7.17 (2H, m), 6.14 (1H, d, J=15.8 Hz), 3.76 (3H, s), 2.62 (2H,q, J=7.6 Hz), 1.21 (3H, t, J=7.6 Hz).

Step 3.Methyl[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-ethyl-2-(phenylsulfonylamino)cinnamate(step 2).

¹H-NMR (CDCl₃) δ: 12.32 (1H, br s), 8.59-8.57 (11H, m), 8.14 (1H, m),7.47-7.39 (2H, m), 7.30-7.21 (2H, m), 4.32 (2H, s), 3.73 (3H, s), 2.75(2H, q, J=7.6 Hz), 2.43 (3H, s), 1.27 (3H, t, J=7.6 Hz).

Example 134[5-Ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 133).

m.p.: 215° C. (decomposed). IR (KBr) ν: 1701, 1638, 1597, 1535, 1443,1420, 1398, 1331, 1279, 1236, 1205 cm⁻¹. ¹H-NMR (DMSO) δ: 12.09 (1H, brs), 8.69 (1H, d, J=4.9 Hz), 7.94 (1H, m), 7.58-7.51 (3H, m), 7.23-7.20(1H, m), 4.06 (2H, s), 2.69 (2H, q, J=7.6 Hz), 2.46 (3H, s), 1.23 (3H,t, J=7.6 Hz).

Example 135Methyl[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate)

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-ethyl-2-(phenylsulfonylamino)cinnamate(Example 133, step 2) and 2-bromoacetyl-4-ethylpyridine (Preparation isdescribed in Example 57).

¹H-NMR (CDCl₃) δ: 12.35 (1H, br s), 8.63 (1H, d, J=5.1 Hz), 8.20 (1H,m), 7.48 (1H, s), 7.42 (1H, d, J=8.6 Hz), 7.34 (1H, dd, J=5.1, 1.8 Hz),7.26-7.22 (1H, m), 4.32 (2H, s), 3.73 (3H, s), 2.76 (4H, q, J=7.6 Hz),1.30 (6H, t, J=7.6 Hz)

Example 136 [5-Ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 135).

m.p.: 206.2° C. IR (KBr) ν: 1703, 1636, 1595, 1533, 1431, 1333, 1283,1236, 1188, 1117cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.09 (1H, br s), 8.73 (1H, d,J=4.9 Hz), 7.97 (1H, s), 7.60-7.52 (3H, m), 7.22 (1H, d, J=8.6 Hz), 4.06(2H, s), 2.82-2.65 (4H, m), 1.28-1.21 (6H, m).

Example 137Methyl[6-ethyl-2-(4-Methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

Step 1. Methyl trans-(4-Acetyl-2-nitro)cinnamate

The title compound was prepared according to the procedure described inExample 131 from 4-bromo-3-nitroacetophenone and methyl acrylate.

¹H-NMR (CDCl₃) δ: 8.58-8.10 (3H, m), 7.77-7.74 (1H, m), 6.48-6.42 (1H,m), 3.85 (3H, s), 2.68 (3H, s).

Step 2. Methyl trans-4-(1-Hydroxyethyl)-2-nitrocinnamate

To a solution of methyl trans-4-acetyl-2-nitrocinnamate (462.2 mg, 1.854mmol) in methanol (55 ml) was added sodium borohydride (176.3 mg, 4.66mmol) at room temperature. After stirring for 10 min, the mixture wasconcentrated. The residue was diluted in dichloromethane (20 ml) andwashed with brine (20 ml) The aqueous layer was extracted withdichloromethane (20 ml×2). The combined organic layers were dried(MgSO₄) and concentrated to afford 442 mg (quant.) of the titlecompound.

¹H-NMR (CDCl₃) δ: 8.12-6.33 (5H, m), 5.0 (1H, m), 3.83 (3H, s), 1.54(3H, d, 9.56 Hz).

Step 3. Methyl trans-(4-Ethyl-2-nitro)cinnamate

To a mixture of sodium iodide (1.668 g, 11.1 mmol) and acetonitrile (581μl, 11.1 mmol) was added chlorotrimethylsilane (1.41 ml, 11.1 mmol) atroom temperature. After stirring for 10 min, a solution of methyltrans-4-(1-hydroxyethyl-2-nitro)cinnamate (563.6 mg, step 1) inhexane-toluene-acetonitrile (1:1:1, 6.0 ml) was added and the mixturewas stirred for an additional 48 h. The reaction mixture was dilutedwith toluene-ethyl acetate (2:3, 25 ml) and poured into water (25 ml).The organic layer was separated and washed with 5% aqueous sodiumthiosulfate (30 ml), brine (30 ml) and dried (MgSO₄). Removal of solventgave 460 mg (quant.) of the title product as a brown oil.

¹H-NMR (CDCl₃) δ: 8.12-6.32 (5H, m), 3.83 (3H, s), 2.76 (2H, q, 7.59Hz), 1.29 (3H, t, 7.59 Hz).

Step 4. Methyl trans-2-Amino-4-ethylcinnamate

The title compound was prepared according to the procedure described instep 2 of Example 36 from methyl trans-4-ethyl-2-nitrocinnamate (step3).

¹H-NMR (CDCl₃) δ: 7.84-6.29 (5H, m), 3.80 (3H, s), 2.57 (2H, m), 1.21(3H, t, 7.59 Hz).

Step 5. Methyl trans-4-Ethyl-2-(p-toluenesulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-2-amino-4-ethylcinnamate (step 4).

¹H-NMR (CDCl₃) δ: 7.57 (2H, d, 8.40 Hz), 7.46 (1H, d, 15.8 Hz),7.39-7.08 (5H, m), 6.43 (1H, s), 6.43 (1H, d, 15.8 Hz), 3.78 (3H, s),2.61 (2H, m), 2.37 (3H, s), 1.18 (3H, t, 7.75 Hz).

Step 6.Methyl[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-ethyl-2-(p-toluenesulfonylamino)cinnamate(step 5) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation isdescribed in step 2 of Example 31).

¹H-NMR (CDCl₃) δ: 12.30 (1H, br s), 8.62 (1H, d, 4.94 Hz), 8.18-7.32(4H, m), 7.05-7.02 (2H, m), 4.33 (2H, s), 3.72 (3H, s), 2.79 (2H, q,7.59 Hz), 2.48 (3H, s), 1.31 (3H, t, 7.59 Hz).

Example 138[6-Ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 137).

m.p.: 204-207° C. IR (KBr) ν: 3240, 1709, 1636, 1593, 1531, 1394, 1204,1144, 1001 cm⁻¹. ¹H-NMR (CDCl₃) δ: 12.07 (1H, br s), 8.69 (1H, d, 4.94Hz), 7.93 (1H, m), 7.63(1H, d, 8.40 Hz), 7.55 (1H, m), 7.45 (1H, s),7.00-6.96(1H, m), 4.05 (2H, s), 2.73 (2H, q, 7.56 Hz), 2.46 (3H, s),1.24 (3H, t, 7.56 Hz).

Example 139Methyl[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

Step 1. Methyl trans-5-Isopropyl-2-aminocinnamate

The title compound was prepared according to the procedure described instep 1 of Example 133 from 2-bromo-4-isopropylaniline.

¹H-NMR (CDCl₃) δ: 7.83 (1H, d, J=15.8 Hz), 7.23 (1H, m), 7.08-7.05 (1H,m), 6.66 (1H, d, J=8.4 Hz), 6.37 (1H, d, J=15.8 Hz), 3.85 (2H, m), 3.81(3H, s), 2.84-2.76 (1H, m), 1.21 (6H, m).

Step 2. Methyl trans-5-Isopropyl-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-5-isopropyl-2-aminocinnamate (step 1).

¹H-NMR (CDCl₃) δ: 7.71-7.68 (2H, m), 7.58 (1H, d, J=15.8 Hz), 7.51-7.20(6H, m), 7.09 (1H, br, s), 6.16 (1H, d, J=15.8 Hz), 4.11 (3H, s),2.94-2.83 (1H, m), 1.24-1.21 (6H, m).

Step 3.Methyl[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-5-isopropyl-2-(phenylsulfonylamino)cinnamate (step 2).

¹H-NMR (CDCl₃) δ: 12.33 (11H, br s), 8.61 (1H, d, J=5.1 Hz), 8.17-8.16(1H, m), 7.50-7.42 (2H, m), 7.33-7.26 (2H, m), 4.32 (2H, s), 3.73 (3H,s), 3.08-2.97 (1H, m), 2.46 (3H, s), 1.33-1.30 (6H, m).

Example 140[5-Isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 139).

m.p.: 213° C. (decomposed). IR (KBr)ν: 1717,1641, 1597, 1537, 1327,1273, 1196cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.10 (1H, br s), 8.70 (1H, d, J=4.9Hz), 7.95-7.94 (1H, m), 7.59-7.54 (2H, m), 7.27 (1H, dd, J=8.6, 1.7 Hz),4.07 (2H, s), 3.03 (1H, m), 2.46 (3H, s), 1.27-1.25 (6H, m).

Example 141Methyl[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate

Step 1. Methyl trans-2-Amino-4-(trifluoromethyl)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 133 from 2-bromo-5-(trifluoromethyl)aniline.

¹H-NMR (CDCl₃) δ: 7.79 (1H, d, J=15.8 Hz), 7.46-7.43 (1H, m), 7.00-6.94(2H, m), 6.41 (1H, d, J=15.8 Hz), 4.18 (2H, m), 3.82 (3H, m).

Step 2. Methyl trans-2-Phenylsulfonylamino-4-(trifluoromethyl)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-2-amino-4-(trifluoromethyl)cinnamate (step 1).

¹H-NMR (CDCl₃) δ: 7.77-7.68 (2H, m), 7.65-7.53 (4H, m), 7.47-7.41 (3H,m), 6.24 (1H, d, J=15.8 Hz), 3.80 (3H, s).

Step 3.Methyl[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-2-phenylsulfonylamino-4-(trifluoromethyl)cinnamate (step 2).

¹H-NMR (CDCl₃) δ: 12.74 (1H, br s), 8.58 (1H, d, J=4.9 Hz), 8.12 (1H,s), 7.81-7.74 (2H, m), 7.35-7.32 (2H, m), 4.32 (2H, s), 3.75 (3H, s),2.46 (3H, s).

Example 142[2-(4-Methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate(Example 141).

m.p.: 210-220° C. IR (KBr) ν: 1697, 1651, 1599, 1537, 1506, 1339, 1283,1196, 1103, 1055 cm⁻¹. ¹H-NMR (DMSO) δ: 12.62 (11H, br s), 8.71 (1H, d,J=4.9 Hz), 8.10 (1H, s), 7.99-7.97 (2H, m), 7.61-7.59 (11H, m),7.39-7.36 (1H, m), 4.14 (2H, s), 2.48 (3H, s).

Example 143Methyl[5-tert-butyl-2-(4-Methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

Step 1. Methyl trans-5-tert-Butyl-2-aminocinnamate

The title compound was prepared according to the procedure described instep 1 of Example 133 from 2-bromo-4-tert-butylaniline.

¹H-NMR (CDCl₃) δ: 7.85 (1H, d, 15.8 Hz), 7.38 (1H, d, 2.30 Hz), 7.23(1H, dd, 8.56 Hz, 2.30 Hz), 6.67 (1H, d, 8.56 Hz), 6.37 (1H, d, 15.8Hz), 3.87 (2H, br s), 3.81 (3H, s), 1.28 (9H, s).

Step 2. Methyl trans-5-tert-Butyl-2-(p-toluenesulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-5-tert-butyl-2-aminocinnamate and p-toluenesulfonyl chloride.

¹H-NMR (CDCl₃) δ: 7.60-7.20 (8H, m), 6.53 (1H, s), 6.17 (1H, d, 15.8Hz), 3.79 (3H, s), 2.46 (3H, s), 1.29 (s, 9H).

Step 3.Methyl[5-tert-Butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The compound was prepared according to the procedure described inExample of 57 from methyltrans-5-tert-butyl-2-(p-toluenesulfonylamino)cinnamate (step 2) and2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described instep 2 of Example 31).

¹H-NMR (CDCl₃) δ: 12.33 (1H, br s), 8.63 (1H, d, 4.94 Hz), 8.18 (1H, m),7.62-7.32 (4H, m), 4.43 (2H, s), 3.74 (3H, s), 2.47 (3H, s), 1.40 (s,9H).

Example 144[5-tert-Butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 143).

m.p.: 191° C. IR (KBr) ν: 2963, 1717, 1645, 1597, 1533, 1437, 1281,1211, 1080, 1032, 1003 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.10 (1H, br s), 7.70(1H, d, 5.11 Hz), 7.95-7.44 (6H, m), 4.09 (2H, s), 2.46 (3H, s), 1.35(9H, s).

Example 145Methyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate

Step 1. Methyl trans-2-Amino-5-(trifluoromethoxy)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 133 from 2-bromo-4-(trifluoromethoxy)aniline.

¹H-NMR (CDCl₃) δ: 7.74 (1H, d, 15.8 Hz), 7.23-7.02 (2H, m), 6.68 (1H, d,8.72 Hz), 6.36 (1H, d, 15.8 Hz), 4.00 (2H, br s), 3.81 (3H, s).

Step 2. Methyltrans-2-2-Toluenesulfonylamino-5-(trifluoromethoxy)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-2-amino-4-(trifluoromethoxy)cinnamate (step 1) andp-toluenesulfonyl chloride.

¹H-NMR (CDCl₃) δ: 7.59-7.19 (8H, m), 6.76 (1H, s), 6.15 (1H, d, 15.8Hz), 3.80 (3H, s), 2.39 (3H, s).

Step 3.Methyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-2-p-toluenesulfonylamino-5-(trifluoromethoxy)cinnamate (step 2)and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation isdescribed in step 2 of Example 31).

¹H-NMR (CDCl₃) δ: 12.7 (1H, br s), 8.64 (1H, d, 5.10 Hz), 8.19 (1H, m),7.55-7.23 (4H, m), 4.30 (2H, s), 3.74 (3H, s), 2.49 (3H, s).

Example 146[2-(4-Methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate(Example 145).

m.p.: 235-238° C. IR (KBr) ν: 3248, 1701, 1645, 1597, 1537, 1447, 1420,1333, 1259, 1203, 1115, 1034, 1003 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.40 (1H,br s), 8.71 (1H, d, 4.94 Hz), 7.97-7.96 (1H, m), 7.80-7.30 (4H, m), 4.09(2H, s), 2.47 (3H, s).

Example 147Methyl[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-2-p-toluenesulfonylamino-5-(trifluoromethoxy)cinnamate (step 2 ofExample 145) and 2-bromoacetyl-4-ethylpyridine (Preparation is describedin Example 57).

¹H-NMR (CDCl₃) 67 : 8.66 (1H, d, 4.97 Hz), 8.22 (1H, br s), 7.55-7.26(4H, m), 4.30 (2H, s), 3.74 (3H, s), 2.79 (2H, q, 7.59 Hz), 1.32 (3H, t,7.59 Hz).

Example 148[2-(4-Ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate(Example 147).

m.p.: 223° C. IR (KBr) ν: 3271, 1697, 1645, 1597, 1539, 1423, 1400,1337, 1258, 1198, 1117, 1028, 1003 cm^(−1.) ¹H-NMR (DMSO-d₆) δ: 12.41(1H, br s), 8.74 (1H, d, 4.94 Hz), 7.99 (1H, m), 7.80-7.75 (2H, m),7.63-7.30 (2H, m), 4.10 (2H, s), 2.78 (2H, q, 7.59 Hz), 1.26 (3H, t,7.59 Hz).

Example 149Methyl[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

Step 1. Methyl trans-2-Amino-4-methylcinnamate

The title compound was prepared according to the procedure described instep 2 of Example 36 from methyl trans-4-methyl-2-nitrocinnamate.

¹H-NMR (CDCl₃) δ: 7.81 (1H, d, J=15.8 Hz), 7.30-7.26 (1H, m), 6.60-6.57(1H, m), 6.52 (1H, m), 6.31 (1H, d, J=15.8 Hz), 3.92 (2H, br s), 3.79(3H, s), 2.26 (2H, s).

Step 2. Methyl trans-4-Methyl-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-2-amino-4-methylcinnamate (step 1).

¹H-NMR (CDCl₃) δ: 7.72-7.68 (2H, m), 7.55-7.49 (1H, m), 7.44-7.34 (4H,m), 7.26-7.22 (1H, m), 7.07-7.04 (1H, m), 6.62 (1H, br s), 6.12 (1H, d,J=15.8 Hz), 3.76 (3H, s), 2.34 (3H, s).

Step 3.Methyl[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-methyl-2-(phenylsulfonylamino)cinnamate(step 2).

¹H-NMR (CDCl₃) δ: 12.26 (1H, br s), 8.61 (1H, d, J=4.9 Hz), 8.17 (1H,m), 7.58 (1H, d, J=8.4 Hz), 7.34-7.29 (2H, m), 7.01-6.98 (1H, m), 4.32(2H, s), 3.72 (3H, s), 2.49 (3H, s), 2.47 (3H, s).

Example 150[6-Methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]Acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 149).

m.p.: 208° C. (decomposed). IR (KBr) ν: 1707, 1638, 1593, 1531, 1277,1205, 1142 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.02 (1H, br s), 8.68 (1H, d,J=4.9 Hz), 7.93 (1H, s), 7.61 (1H, d, J=8.2 Hz), 7.56-7.54 (1H, m), 7.42(1H, s), 6.96-6.93 (1H, m), 4.04 (2H, s), 2,46 (3H, s), 2.43 (3H, s).

Example 151Methyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate

Step 1. Methyl trans-2-Amino-5-(trifluoromethyl)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 133 from 2-bromo-4-(trifluoromethyl)aniline.

¹H-NMR (CDCl₃) δ: 7.77 (1H, d, J=15.8 Hz), 7.61 (1H, s), 7.39 (1H, d,J=8.4 Hz), 6.74 (1H, d, J=8.4 Hz), 6.41 (1H, dd, J=15.8, 1.5 Hz), 4.29(2H, m), 3.82 (3H, m).

Step 2. Methyl trans-2-Phenylsulfonylamino-5-(trifluoromethyl)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-2-amino-5-(trifluoromethyl)cinnamate (step 1).

¹H-NMR (CDCl₃) δ: 7.79-7.76 (2H, m), 7.66 (1H, m), 7.60-7.44 (6H, m),7.06 (1H, br s), 6.26 (1H, d, J=15.8 Hz), 3.81 (3H, s).

Step 3.Methyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-2-phenylsulfonylamino-5-(trifluoromethyl)cinnamate (step 2).

¹H-NMR (CDCl₃) δ: 12.70 (1H, br s), 8.62 (1H, d, J=4.9 Hz), 8.17 (1H,s), 8.00 (1H, s), 7.61-7.54 (2H, m), 7.38-7.36 (1H, m), 4.34 (2H, s),3.75 (3H, s), 2.48 (3H, s).

Example 152[2-(4-Methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate(Example 151).

m.p.: 218-225° C. IR (KBr) ν: 1697, 1645, 1599, 1541, 1337, 1277,1202,1161, 1111, 1053 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.52 (1H, br s), 8.71 (1H,d, J=4.9 Hz), 8.23 (1H, s), 7.97 (1H, m), 7.85 (1H, d, J=8.9 Hz),7.62-7.58 (2H, m), 4.16 (2H, s), 2.48 (3H, s).

Example 153Methyl[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-2-phenylsulfonylamino-5-(trifluoromethyl)cinnamate (step 2 ofExample 151) and 2-bromoacetyl-4-ethylpyridine (Preparation is describedin Example 57).

¹H-NMR (CDCl₃) δ: 12.65 (1H, br s), 8.64 (1H, d, J=5.1 Hz), 8.21 (1H,m), 8.01 (1H, s), 7.61-7.52 (2H, m), 7.40-7.37 (1H, m), 4.34 (2H, s),3.76 (3H, s), 2.78 (2H, q, J=7.6 Hz), 1.31 (3H, t, J=7.6 Hz).

Example 154[2-(4-Ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate(Example 153).

m.p.: 203.6° C. IR (KBr) ν: 1703, 1647, 1599, 1537, 1340, 1202, 1105,1051 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.52 (1H, br s), 8.74 (1H, d, J=5.1 Hz),8.24 (1H, s), 8.00-7.99 (1H, m), 7.86 (1H, d, J=8.7 Hz), 7.64-7.58 (2H,m), 4.16 (2H, s), 2.79 (2H, q, J=7.6 Hz), 1.26 (3H, t, J=7.6 Hz).

Example 155 Methyl(2-benzoyl-1H-indol-3-yl)acetate

Step 1. Methyl trans-2-(Phenylsulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyl trans-2-aminocinnamate.

¹H-NMR (CDCl₃) δ: 7.71-7.67 (2H, m), 7.58 (1H, d, J=15.8 Hz), 7.52-7.32(6H, m), 7.28-7.22 (1H, m), 7.08 (1H, br s), 6.15 (1H, d, J=15.8 Hz),3.78 (3H, s).

Step 2. Methyl(2-benzoyl-1H-indol-3-yl)acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-2-(phenylsulfonylamino)cinnamate (step 1).

¹H-NMR (CDCl₃) δ: 8.91 (1H, br s), 7.80-7.77 (2H, m), 7.67-7.58 (2H, m),7.53-7.48 (2H, m), 7.43-7.34 (2H, m), 7.21-7.15 (1H, m), 3.86 (2H, s),3.65 (3H, s).

Example 156 (2-Benzoyl-1H-indol-3-yl)acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) from methyl(2-benzoyl-1H-indol-3-yl)acetate(Example 155).

m.p.: 194-196° C. IR (KBr) ν: 1713, 1597, 1541, 1450, 1402, 1267, 1180,729 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.62 (1H, br s), 7.77-7.74 (2H, m),7.69-7.66 (2H, m), 7.60-7.55 (2H, m), 7.48-7.45 (1H, m), 7.34-7.28 (1H,m), 7.13-7.08 (1H, m), 3.80 (2H, s).

Example 157 Methyl[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-methyl-2-(phenylsulfonylamino)cinnamate(step 2 of Example 149) and 4-chlorophenacyl bromide.

¹H-NMR (CDCl₃) δ: 8.84 (1H, br s), 7.74-7.71 (2H, m), 7.53-7.45 (3H, m),7.14 (1H, m), 7.03-7.00 (1H, m), 3.81 (2H, s), 3.65 (3H, s), 2.46 (3H,s).

Example 158 [2-(4-Chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate (Example 157).

m.p.: 193-195° C. IR (KBr) ν: 3302, 1697, 1587, 1335, 1263, 1090, 999,770 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.47 (1H, br s), 7.76-7.73 (2H, m),7.65-7.61 (2H, m), 7.57 (1H, d, J=8.4 Hz), 7.23 (1H, s), 6.96-6.93 (1H,m), 3.79 (2H, s), 2.42 (3H, s).

Example 159 [2-(4-Chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic Acid

Step 1. 2-(4-Chlorobenzoyl)-5-methyl-1-(phenylsulfonyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 2 (Method B) from 5-methyl-1-(phenylsulfonyl)indole(E. Wenkert, P. Moeller, and S. Piettre, J. Am. Chem. Soc., 1988, 110,7188-7194) and 4-chlorobenzoyl chloride.

¹H-NMR (CDCl₃) δ: 8.02-7.96 (3H, m), 7.96-7.88 (2H, m), 7.57-7.43 (5H,m), 7.33-7.25 (2H, m), 6.88 (1H, s), 2.41 (3H, s).

Step 2. 2-(4-Chlorobenzoyl)-5-methylindole

The title compound was prepared according to the procedure described instep 3 of Example 2 (Method B) from2-(4-chlorobenzoyl)-5-methyl-1-(phenylsulfonyl)indole (step 1).

¹H-NMR (CDCl₃) δ: 9.43 (1H, br s), 7.94-7.91 (2H, m), 7.51-7.47 (3H, m),7.37 (1H, d, J=8.4 Hz), 7.21 (1H, dd, J=8.4, 1.5 Hz), 7.04-7.03 (1H, m),2.44 (3H, s).

Step 3. Diethylα-Acetoxy-[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 2-(4-chlorobenzoyl)-5-methylindole(step 3).

¹H-NMR (CDCl₃) δ: 8.74 (11H, br s), 7.79 (2H, d, J=8.4 Hz), 7.67 (I1H,s), 7.42 (2H, d, J=8.4 Hz), 7.27-7.24 (1H, m), 7.14-7.11 (1H, m),4.244.16 (4H, m), 2,45 (3H, s), 1.28-1.18 (6H, m).

Step 4. Diethyl[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]malonate (step 3).

¹H-NMR (CDCl₃) δ: 8.80 (1H, br s), 7.73 (2H, d, J=8.4 Hz), 7.54 (1H, s),7.47 (2H, d, J=8.4 Hz), 7.21-7.18 (1H, m), 7.13-7.10 (1H, m), 4.25-4.13(4H, m), 2.42 (3H, s), 1.28-1.21 (6H, m).

Step 5. [2-(4-Chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]malonate (step 4).

m.p.: 194-197° C. IR (KBr) ν: 3308, 1695, 1609, 1529, 1402, 1263, 1223,1088, 1015 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.18 (1H, br s), 11.49 (1H, s),7.77-7.73 (2H, m), 7.66-7.62 (2H, m), 7.45 (1H, s), 7.35 (1H, d, J=8.6Hz), 7.15 (1H, dd, J=8.6, 1.5 Hz), 3.81 (2H, s), 2.39 (3H, s).

Example 160 Methyl[6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-4-methoxy-3-p-toluenesulfonylamino)cinnamate (step 3 of Example131) and 4-chlorophenacyl bromide.

¹H-NMR (CDCl₃) δ: 8.89 (1H, br s), 7.74-7.43 (5H, m), 6.86-6.77 (m, 2H),3.85 (3H, s), 3.79 (3H, s), 3.65 (3H, s).

Example 161 [6-Methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate (Example160).

m.p.: 193° C. IR (KBr) ν: 3308, 1701, 1628, 1603, 1526, 1427, 1335,1271, 1205, 1148, 1092, 1032, 999 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.43 (1H,br s), 7.75-7.56 (5H, m), 6.87 (1H, d, 2.13 Hz), 7.76 (1H, dd, 8.88 Hz,2.13 Hz), 3.80 (3H, s), 3.79 (2H, s).

Example 162 [2-(4-Chlorobenzoyl)-6-trifluoromethyl-1H-indol-3-yl]aceticAcid

Step 1. 1-Phenylsulfonyl-6-(trifluoromethyl)indole

To a stirred mixture of 6-(trifluoromethyl)indole (500 mg, 2.70 mmol),50% aqueous sodium hydroxide (5 ml), water (7 ml), andtetrabutylammonium bromide (87 mg, 0.27 mmol) was added a solution ofphenylsulfonyl chloride (379 μl, 2.97 mmol) in toluene (5 ml) at roomtemperature. After stirring for 1 h, the organic layer was separated.The aqueous layer was extracted with ethyl acetate (50 ml). The combinedorganic layers were washed with saturated sodium bicarbonate (30 ml),water (30 ml), brine (30 ml), dried (MgSO₄), and concentrated to give835 mg (95%) of the title compound.

¹H-NMR (CDCl₃) δ: 8.29 (1H, s), 7.91-7.88 (2H, m), 7.71 (1H, d, J=3.6Hz), 7.64-7.54 (2H, m), 7.49-7.44 (3H, m), 6.72 (1H, d, J=3.6 Hz).

Step 2. 2-(4-Chlorobenzoyl)-1-phenylsulfonyl-6-(trifluoromethy)indole

The title compound was prepared according to the procedure described instep 2 of Example 2 (Method B) from1-phenylsulfonyl-6-(trifluoromethyl)indole (step 1).

¹H-NMR (CDCl₃) δ: 8.42 (1H, s), 8.05-8.01 (2H, m), 7.92-7.89 (2H, m),7.71-7.47 (7H, m), 6.95 (1H, s).

Step 3. 2-(4-Chlorobenzoyl)-6-(trifluoromethyl)indole

The title compound was prepared according to the procedure described instep 3 of Example 2 (Method B) from2-(4-chlorobenzoyl)-1-phenylsulfonyl-6-(trifluoromethyl)indole (step 2).

¹H-NMR (CDCl₃) δ: 9.53 (1H, br s), 7.99-7.95 (2H, m), 7.85-7.79 (2H, m),7.56-7.53 (2H, m), 7.42-7.39 (1H, m), 7.19-7.18 (1H, m).

Step 4. Diethylα-Acetoxy-[2-(4-chlorobenzoyl)-6-(trifluoromethyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from2-(4-chlorobenzoyl)-6-(trifluoromethyl)indole (step 3).

¹H-NMR (CDCl₃) δ: 9.27 (1H, br s), 8.00 (1H, d, J=8.7 Hz), 7.78 (2H, d,J=8.6 Hz), 7.68 (1H, s), 7.45-7.39 (3H, m), 4.24-4.12 (4H, m), 1.74 (3H,s), 1.21-1.14 (6H, m).

Step 5.Diethyl[2-(4-chlorobenzoyl)-6-(trifluoromethyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy-[2-(4-chlorobenzoyl)-6-trifluoromethyl)-1H-indol-3-yl]malonate(step 4).

¹H-NMR (CDCl₃) δ: 9.37 (1H, br s), 7.83 (1H, d, J=8.6 Hz), 7.77-7.73(2H, m), 7.51-7.48 (3H, m), 7.33-7.30 (1H, m), 5.27 (1H, s), 4.25-4.06(4H, m), 1.31-1.15 (6H, m).

Step 6. [2-(4-Chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[2-(4-chlorobenzoyl)-6-(trifluoromethyl)-1H-indol-3-yl]malonate(step 5).

m.p.: 155-160° C. IR (KBr) ν: 3379, 1705, 1611, 1589, 1516, 1337, 1229,1119, 1092, 1055 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.09 (1H, br s), 7.96-7.93(1H, m), 7,82-7.78 (3H, m), 7.68-7.64 (2H, m), 7.41-7.37 (1H, m), 3.86(2H, s).

Example 163 Methyl[2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-ethyl-2-(phenylsulfonylamino)cinnamate(Example 133, step 2).

¹H-NMR (CDCl₃) δ: 8.86 (1H, br s), 7.74-7.71 (2H, m), 7.48-7.41 (3H, m),7.32-7.21 (2H, m), 3.85 (2H, s), 3.66 (3H, s), 2.75 (2H, q, J=7.6 Hz),1.28 (3H, t, J=7.6 Hz)

Example 164 [2-4-Chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 from methyl[2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetate(Example 163).

m.p.: 165-168° C. IR (KBr): 3321, 1693, 1605, 1531, 1221, 1088, 1011cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.49 (1H, br s), 7.76-7.72 (2H, m), 7.65-7.61(2H, m), 7.46 (1H, m), 7.36 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=8.6, 1.5Hz), 3.81 (2H, s), 2.67 (2H, q, J=7.6 Hz), 1.21 (3H, t, J=7.6 Hz).

Example 165 Methyl[2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-methoxy-2-(phenylsulfonylamino)cinnamate(Example 129, step 3).

¹H-NMR (CDCl₃) δ: 8.81 (1H, br s), 7.75-7.72 (2H, m), 7.49-7.46 (2H, m),7.29 (1H, d, J=8.9 Hz), 7.04 (1H, dd, J=8.9, 2.5 Hz), 6.98 (1H, d, J=2.5Hz), 3.86 (3H, s), 3.85 (2H, s), 3.67 (3H, s).

Example 166 [2-(4-Chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetate (Example165).

m.p.: 200-204° C. IR (KBr) ν: 3325, 1724, 1607, 1526, 1429, 1356, 1265,1229, 1092, 1011 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.46 (1H, br s), 7.74 (2H,d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz), 7.35 (1H, d, J=8.9 Hz), 7.13 (1H,d, J=2.5 Hz), 6.96 (1H, dd, J=8.9, 2.5 Hz), 3.83 (2H, s), 3.77 (3H, s).

Example 167 Methyl[2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-5-isopropyl-2-(phenylsulfonylamino)cinnamate (Example 139, step2).

¹H-NMR (CDCl₃) δ: 8.87 (1H, br s), 7.74-7.70 (2H, m), 7.49-7.44 (3H, m),7.33-7.25 (2H, m), 3.85 (2H, s), 3.66 (3H, s), 3.07-2.96 (1H, m),1.32-1.29 (6H, m).

Example 168 [2-(4-Chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetate (Example169).

m.p.: 197-200° C. IR (KBr) ν: 1697, 1609, 1533, 1429, 1348, 1265, 1090,1011 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.18 (1H, br s), 11.50 (1H, br s),7.77-7.74 (2H, m), 7.65-7.62 (2H, m), 7.50 (1H, m), 7.40-7.37 (1H, m),7.26-7.23 (1H, m), 3.83 (2H, s), 3.03-2.92 (1H, m), 1.26-1.24 (6H, m).

Example 169Methyl[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-2-phenylsulfonylamino-5-(trifluoromethyl)cinnamate (Example 151,step 2).

¹H-NMR (CDCl₃) δ: 9.34 (1H, br s), 7.90 (1H, s), 7.77-7.70 (2H, m),7.51-7.43 (3H, m), 7.33 (1H, d, J=8.7 Hz), 3.85 (2H, s), 3.66 (3H, s).

Example 170 [2-(4-Chlorobenzoyl)-5-trifluoromethyl-1-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate(Example 169).

m.p.: 198-200° C. IR (KBr) ν: 3317, 1697,1611, 1333, 1271, 1113, 1051,1007 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.08 (1H, br s), 8.18 (1H, s), 7.80-7.77(2H, m), 7.68-7.57 (4H, m), 3.92 (2H, s).

Example 171Methyl[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-3-p-toluenesulfonylamino-5-(trifluoromethoxy)cinnamate (Example145, step 2) and 4-chlorophenacyl bromide.

¹H-NMR (CDCl₃) δ: 8.93 (1H, br s), 7.76 (2H, d, 8.75 Hz), 7.52-7.40 (5H,m), 3.82 (2H, s), 3.68 (3H, s).

Example 172 [2-(4-Chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate(Example 171).

m.p.: 195° C. IR (KBr) ν: 3339, 1705, 1622, 1589, 1533, 1435, 1342,1256, 1225, 1177, 1092, 1013 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.91 (1H, br s),7.80-7.64 (5H, m), 7.55 (1H, d, 8.91 Hz), 7.32-7.24 (m, 1H), 3.87 (2H,s).

Example 173 Methyl[6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetate

Step 1. Methyl 2-[6-Chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 2-methoxyphenacyl bromide.

¹H-NMR (CDCl₃) δ: 9.02 (1H, br s), 7.60-7.46 (2H, m), 7.42-7.34 (2H, m),7.15-6.99 (3H, m), 3.78 (3H, s), 3.66 (2H, s), 3.60 (3H, m).

Example 174 [6-Chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetate (Example172).

m.p.: 214-217° C. IR (KBr) ν: 3398, 2939, 2642, 1711, 1680, 1624, 1537,1461, 1315, 1230, 937 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.61 (1H, s), 7.67 (1H,d, J=8.7 Hz), 7.60-7.51 (1H, m), 7.45 (1H, d, J=2.0 Hz), 7.28 (1H, dd,J=7.4, 1.6 Hz), 7.18 (1H, d, J=8.2 Hz), 7.12-7.04 (2H, m), 3.70 (3H, s),3.60 (2H, s).

Example 175 Methyl[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 3-methoxyphenacyl bromide.

¹H-NMR (CDCl₃) δ: 8.86 (1H, s), 7.57 (1H, d, J=8.7 Hz), 7.46-7.26 (4H,m), 7.19-7.12 (2H, m), 3.86 (3H, s), 3.83 (2H, s), 3.67 (3H, s).

Example 176 [6-Chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetate (Example175).

m.p.: 227-231° C. IR (KBr) ν: 3354, 2933, 2636, 1709, 1607, 1569, 1427,1321, 1269, 1218, 1049 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.76 (1H, s), 7.72(1H, d, J=8.6 Hz), 7.54-7.45 (2H, m), 7.35-7.22 (3H, m), 7.16-7.10 (1H,m), 3.83 (3H, s), 3.79 (2H, s).

Example 177 Methyl[6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 3-benzyloxyphenacyl bromide (A.Hernandez et al., J. Org. Chem., 1994, 59, 1058).

¹H-NMR (CDCl₃) δ: 8.79 (1H, s), 7.56 (1H, d, J=8.6 Hz), 7.46-7.33 (9H,m), 7.26-7.19 (1H, m), 7.16 (1H, dd, J=8.6, 1.8 Hz), 5.12 (2H, s), 3.82(2H, s), 3.64 (3H, s).

Example 178 [6-Chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) from methyl2-[6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetate (Example 177).

m.p.: 174-177° C. IR (KBr) ν: 3308, 3028, 2897, 1697, 1612, 1566, 1444,1328, 1269, 1223, 732 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.76 (1H, s), 7.71 (1H,d, J=8.6 Hz), 7.54-7.30 (10H, m), 7.13 (1H, dd, J=8.6, 1.6 Hz), 5.18(2H, s), 3.78 (2H, s).

Example 179 Methyl[6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetate

A mixture ofmethyl[6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetate (Example177, 0.37 g, 0.85 mmol) and 10% palladium-charcoal (80 mg) in ethylacetate-methanol (5:1, 30 ml) was stirred under hydrogen atmosphere for2.5 h. The mixture was filtered thorough a pad of Celite and thefiltrate was concentrated. The solids were washed with dichloromethane(10 ml) to afford 70mg (24%) of the title compound as white solids.

¹H-NMR (CDCl₃) δ: 10.36 (1H, br s), 9.06 (1H, s), 7.55 (1H, d, J=8.7Hz), 7.50-7.46 (1H, m), 7.36-7.22 (3H, m), 7.15-7.05 (2H, m), 3.89 (2H,s), 3.65 (3H, s).

Example 180 [6-Chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetate (Example179).

m.p.: 213-215° C. IR (KBr) ν: 3311, 3069, 1715, 1624, 1583, 1529, 1448,1325, 1278, 1220, 761 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.71 (1H, s), 9.86 (1H,br s), 7.71 (1H, d, J=8.6 Hz), 7.47 (1H, d, J=1.5 Hz), 7.41-7.32 (1H,m), 7.20-7.02 (4H, m), 3.82 (2H, s).

Example 181 Methyl[6-chloro-2-(4-benzyloxybenzoyl-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 4-benzyloxyphenacyl bromide (A.Brossi et al., J. Heterocycl. Chem., 1965, 2, 310).

¹H-NMR (CDCl₃) δ: 8.87 (1H, br s), 7.81 (2H, d, J=8.6 Hz), 7.55 (1H, d,J=8.7 Hz), 7.48-7.32 (6H, m), 7.14 (1H, dd, J=8.7, 1.8 Hz), 7.06 (2H, d,J=8.6 Hz), 5.16 (2H, s), 3.86 (2H, s), 3.65 (3H, s).

Example 182 [6-Chloro-2-(4-benzyloxybenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) from methyl2-[6-chloro-2-(4-benzyloxybenzoyl)-1H-indol-3-yl]acetate (Example 181).

m.p.: 220-222° C. IR (KBr) ν: 3331, 3013, 2914, 1717, 1699, 1599, 1564,1508, 1253, 1167, 941 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.72 (1H, s), 7.76 (2H,d, J=8.9 Hz), 7.69 (1H, d, J=8.4 Hz), 7.52-7.32 (6H, m), 7.17 (2H, d,J=8.9 Hz), 7.11 (1H, dd, J=8.4, 2.2 Hz), 5.23 (2H, s), 3.81 (2H, s).

Example 183 Methyl[6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 179 frommethyl[6-chloro-2-(4-benzyloxybenzoyl)-1H-indol-3-yl]acetate (Example181).

¹H-NMR (acetone-d₆) δ: 10.82 (1H, br s), 9.21 (1H, br s), 7.75 (2H, d,J=8.7 Hz), 7.71 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=2.0 Hz), 7.13 (1H, dd,J=8.7, 2.0 Hz), 6.97 (2H, d, J=8.7 Hz), 3.95 (2H, s), 3.59 (3H, s).

Example 184 [6-Chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetate (Example183).

m.p.: 231-234° C. IR (KBr) ν: 3250 3120, 2822, 1734, 1618, 1539, 1456,1321, 1236, 1120, 1060cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.58 (1H, br s),7.63-7.53 (3H, m), 7.35 (1H, d, J=1.9 Hz), 7.00 (1H, dd, J=8.6, 1.9 Hz),6.80 (2H, d, J=8.9 Hz), 3.69 (2H, s).

Example 185Methyl[6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetate

To a stirred solution ofmethyl[6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetate (Example 183,0.15 g, 0.44 mmol) in DMF (5 ml) was added sodium hydride (15 mg, 0.46mmol) at room temperature under nitrogen atmosphere. After 5min.,2-iodopropane (78 mg) was added and the mixture was stirred for 7 h. Themixture was quenched with 2N aqueous HCl (20 ml), and extracted withethyl acetate (50 ml). The extract was washed with water (30 ml) andbrine (30 ml), dried (MgSO₄), and concentrated. The residue was purifiedby flash column chromatography eluting with ethyl acetate-hexane (1:2)to afford 72 mg (43%) of the title compound as white solids.

¹H-NMR (CDCl₃) δ: 8.81 (1H, br s), 7.80 (2H, d, J=8.9 Hz), 7.56 (1H, d,J=8.7 Hz), 7.41 (1H, d, J=1.8 Hz), 7.15 (1H, dd, J=8.7, 1.8 Hz), 6.95(2H, d, J=8.9 Hz), 4.67 (1H, heptet, J=6.1 Hz), 3.87 (2H, s), 3.67 (3H,s) 1.39 (6H, d, J=6.1 Hz).

Example 186 [6-Chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetate (Example185).

m.p.: 216-218° C. IR (KBr) ν: 3304, 2972, 2881, 1707, 1614, 1596, 1560,1508, 1311, 1261, 1163cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.71 (1H, br s), 7.75(2H, d, J=8.9 Hz), 7.69 (1H, d, J=8.6 Hz), 7.46 (1H, d, J=2.0 Hz), 7.12(1H, dd, J=8.6, 2.0 Hz), 7.07 (2H, d, J=8.9 Hz), 4.78 (1H, heptet, J=5.9Hz), 3.82 (2H, s) 1.32 (6H, d, J=5.9 Hz).

Example 187 Methyl[6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 4-phenylphenacyl bromide.

¹H-NMR (CDCl₃) δ: 8.91 (1H, br s), 7.88 (2H, d, J=8.1 Hz), 7.73 (2H, d,J=8.1Hz), 7.68-7.38 (7H, m), 7.16 (1H, dd, J=8.1, 1.8 Hz), 3.89 (2H, s),3.66 (3H, s).

Example 188 [6-Chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetate (Example 187).

m.p.: 228-231° C. IR (KBr ) ν: 3317, 3030, 2868, 1707, 1620, 1600, 1527,1431, 1323, 1256, 1194 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.81 (1H, s), 7.89(2H, d, J=8.6 Hz), 7.87 (2H, d, J=8.6 Hz), 7.82-7.72 (3H, m), 7.58-7.40(4H, m), 7.14 (1H, dd, J=8.6, 1.8 Hz), 3.87 (2H, s).

Example 189Methyl[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 4-(trifluoromethoxy)phenacylbromide*.

* 4-(Trifluoromethoxy)phenacyl bromide was prepared as follows;

¹H-NMR (CDCl₃) δ: 8.85 (1H, br s), 7.85 (2H, d, J=8.9 Hz), 7.57 (1H, d,J=8.6 Hz), 7.40 (1H, d, J=1.8 Hz), 7.35 (2H, d, J=8.9 Hz), 7.16 (1H, dd,J=8.6, 1.8 Hz), 3.80 (2H, s), 3.65 (3H, s).

A mixture of 4-(trifluoromethoxy)acetophenone (0.52 g, 2.55 mmol) andtetrabutylammonium tribromide (1.35 , 2.80 mmol) indichloromethane-methanol (1:1, 8 ml) was stirred for 18 h and thenconcentrated. The residue was diluted with ethyl acetate (50 ml), washedwith water (50 ml), brine (50 ml), and dried (MgSO₄). Removal of solventgave 0.36 g (50%) of the title compound as a yellow oil.

tlc: Rf=0.47 (hexane-ethyl acetate=10:1).

Example 190 [6-Chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-(4-trifluoromethoxybenzoyl)1H-indol-3-yl]acetate(Example 189).

m.p.: 166-168° C. IR (KBr) ν: 3315, 3219, 1719, 1699, 1616, 1527, 1508,1254, 1221, 1167, 943 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.79 (1H, s), 7.88 (2H,d, J=8.6 Hz), 7.75 (1H, d, J=8.9 Hz), 7.56 (2H, d, J=8.6 Hz), 7.47 (1H,d, J=1.8 Hz), 7.14 (1H, dd, J=8.9, 1.8 Hz), 3.85 (2H, s).

Example 191Methyl[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 8 (Method B) from methyl trans5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and4-(trifluoromethoxy)phenacyl bromide (Preparation is described inExample 189).

¹H-NMR (CDCl₃) δ: 8.92 (1H, br s), 7.85 (2H, d, J=8.7 Hz), 7.61 (1H, brs), 7.38-7.28 (4H, m), 3.79 (2H, s), 3.67 (3H, s).

Example 192 [5-Chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate(Example 191).

m.p.: 186.7° C. IR (KBr) ν: 3332, 3086, 2925, 1697, 1610, 1408, 1259,1217, 1161, 1007, 941 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.85 (1H, br s), 7.89(2H, d, J=8.7 Hz), 7.81 (1H, d, J=2.1 Hz), 7.60-7.53 (2H, m), 7.48 (1H,d, J=8.7Hz), 7.32 (1H, dd, J=8.7, 2.1 Hz), 3.86 (2H, s).

Example 193 Methyl[6-chloro-2-(4-methoxybenzoylpnenol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans 5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 4-methoxyphenacyl bromide.

¹H-NMR (CDCl₃) δ: 8.86 (1H, s), 7.82 (2H, d, J=8.9 Hz), 7.63-7.60 (1H,m), 7.37-7.26 (2H, m), 6.99 (2H, d, J=8.9 Hz), 3.90 (3H, s), 3.84 (2H,s), 3.69(3H, s).

Example 194 [5-Chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate (Example193).

m.p.: 232-235° C. IR (KBr) ν: 3312, 2833, 2621, 1701, 1599, 1510, 1454,1263, 1167, 1001, 777 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.78 (1H, s), 7.78 (2H,d, J=8.9 Hz), 7.75 (1H, d, J=2.0 Hz), 7.47 (1H, d, J=8.7 Hz), 7.29 (1H,dd, J=8.7, 2.0 Hz), 7.11 (2H, d, J=8.9 Hz), 3.88 (3H, s), 3.82 (2H, s).

Example 195 Methyl[6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 4-nitrophenacyl bromide.

¹H-NMR (CDCl₃) δ: 8.92 (1H, br s), 8.37 (2H, d, J=8.9 Hz), 7.93 (2H, d,J=8.9 Hz), 7.57 (1H, d, J=8.7 Hz), 7.40 (1H, d, J=1. 8 Hz), 7.18 (1H,dd, J=8.7, 1.8 Hz), 3.73 (2H, s), 3.65 (3H, s).

Example 196 [6-Chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate (Example 195).

m.p.: 218.9° C. (decomposed). IR (KBr) ν: 3365, 3101, 2846, 1718, 1699,1647, 1537, 1348, 1255, 1227, 852 m⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.84 (1H,s), 8.38 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.9 Hz), 7.78 (1H, d, J=8.6Hz), 7.48 (1H, d, J=2.0 Hz), 7.15 (1H, dd, J=8.6, 2.0 Hz), 3.83 (2H, s).

Example 197Methyl[6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from 4-(methylsulfonyl)phenacyl bromide.

¹H-NMR (CDCl₃) δ: 9.10 (1H, br s), 8.08 (2H, d, J=8.6 Hz), 7.93 (2H, d,J=8.3 Hz), 7.57 (1H, d, J=8.7 Hz), 7.37 (1H, br), 7.20-7.10 m(1H, m),3.78 (2H, s), 3.64 (3H, s), 3.12 (3H, s).

Example 198 [6-Chloro-2-[(4-methylsulfonyl)benzoyl-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 9 (method B) frommethyl[6-chloro-2-(4-methylsulfonyl)benzoyl-1H-indol-3-yl]acetate(Example 197).

m.p.: 241° C. (decomposed). IR (KBr) ν: 3330, 1713, 1614, 1524, 1230,1150, 941, 781 cm¹. ¹H-NMR (DMSO-d₆) δ: 11.83 (1H, s), 8.12 (2H, d,J=8.3 Hz), 7.96 (2H, d, J=8.3 Hz), 7.78 (1H, d, J=8.7 Hz), 7.48 (1H, d,J=1.8 Hz), 7.15 (1H, dd, J=1.8, 8.7 Hz), 3.85 (2H, s), 3.33 (3H, s).

Example 199Methyl[6-Chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 8 (Method B) from methyltrans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8,Method A) and 4-(methylsulfonylamino)phenacyl bromide*.

* 4-(Methylsulfonylamino)phenacyl bromide was prepared from(4-acetylphenyl)methanesulfonamide (R. Lis, et al., J. Org. Chem., 1987,52, 4377) according to the procedure for preparing4-(trifluoromethoxy)phenacyl bromide described in Example 189.

¹H-NMR (CDCl₃) δ: 8.86 (1H, br s), 7.82 (2H, d, J=8.72 Hz), 7.58 (1H, d,J=8.72 Hz), 7.42-7.15(4H, m), 6.80(1H, br s), 3.83 (2H, s), 3.67(3H, s),3.13 (3H, s). ¹H-NMR (CDCl₃) δ: 8.01 (2H, d, 8.72 Hz), 7.28 (2H, d, 8.72Hz), 4.40 (2H, s), 3.13 (2H, s).

Example 200[6-Chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetate(Example 199).

m.p.: 207-210° C. IR (KBr) ν: 3333, 3248, 1715, 1603, 1570, 1529, 1508,1394, 1323, 1259, 1231, 1159, 1061 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.6 (1H,br s), 7.76 (2H, d, J=8. 88 Hz), 7.71 (1H, d, J=8.56 Hz), 7.46 (1H, 1.65Hz), 7.12 (1H, dd, J=8.56 Hz, 1.65 Hz), 3.81 (2H, s), 3.13 (3H, s).

Example 201 [6-Chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 6-Chloro-2-(2-chlorobenzoyl)-1-(phenylsulfonyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 1 (Method B) from 6-chloro-1-(phenylsulfonyl)indole(step 1 of Example 1, Method B) and 2-chlorobenzoyl chloride. The crudeproduct was used for the next step without further purification.

tlc: Rf=0.25 (hexane-ethyl acetate=4:1).

Step 2. 6-Chloro-2-(2-chlorobenzoyl)indole

The title compound was prepared according to the procedure described instep 3 of Example 1 (Method B) from6-chloro-2-(2-chlorobenzoyl)-1-(phenylsulfonyl)indole (step 1). Thecrude product was used for the next step without further purification.

tlc: Rf =0.37 (hexane-ethyl acetate=4:1)

Step 3. Diethylα-Acetoxy-2-[6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 1 (Method B) from 6-chloro-2-(2-chlorobenzoyl)indole(step 2).

¹H-NMR (CDCl₃) δ: 8.61 (1H, br s), 7.79(1H, d, J=8.88 Hz), 7.52-7.33(5H, m), 7.15 (1H, dd, J=1.97 Hz, 8.88 Hz), 4.26 (4H, m), 2.02 (3H, s),1.22 (6H, t, J=7.07 Hz).

Step 4. Diethyl[6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 1 (Method B) from diethylα-acetoxy-[6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]malonate (step 3).

¹H-NMR (CDCl₃) δ: 8.95 (1H, br s), 7.75 (1H, d, J=8.88 Hz), 7.53-7.39(5H, m), 4.83 (1H, s), 4.15 (4H, m), 1.20 (6H, t, J=7.26 Hz).

Step 5. 2-[6-Chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]acetic Aid

The compound was prepared according to the procedure described in step 6of Example 1 (Method B) fromdiethyl[6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]malonate (step 4).

m.p.: 138-140_C. IR (KBr) ν: 3315, 1713, 1632, 1564, 1526, 1435, 1325,1254, 1215, 1151, 1061 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.67 (1H, s), 7.61(1H,d, J=8.72), 7.51-7.34 (5H, m), 7.50 (1H, dd, J=1.97, 8.72 Hz), 3.75 (2H,s).

Example 202 [6-Chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. 6-Chloro-2-(2,4-dichlorobenzoyl)-1-(phenylsulfonyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 1 (Method B) from 6-chloro-1-(phenylsulfonyl)indole(step 1 of Example 1, Method B) and 2,4-dichlorobenzoyl chloride. Thecrude product was used for the next step without further purification.

tlc: Rf =0.34 (hexane-ethyl acetate =4:1).

Step 2. 6-Chloro-2-(2,4-dichlorobenzoyl)indole

The title compound was prepared according to the procedure described instep 3 of Example 1 (Method B) from6-chloro-2-(2,4-dichlorobenzoyl)-1-(phenylsulfonyl)indole (step 1). Thecrude product was used for the next step without further purification.

tlc: Rf=0.45 (hexane-ethyl acetate=4:1)

Step 3. Diethylα-Acetoxy-[6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 1 (Method B) from6-chloro-2-(2,4-dichlorobenzoyl)indole (step 2).

¹-NMR (CDCl₃) δ: 8.92 (1H, br s), 7.79-7.11(6H, m), 4.24 (4H, m), 2.02(3H, s), 1.22 (6H, t, J=7.10 Hz).

Step 4. Diethyl[6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 1 from diethylα-acetoxy-[6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]malonate (step3).

¹H-NMR (CDCl₃) δ: 8.92 (1H, br s), 7.75 (1H, d, J=8.92 Hz), 7.55-7.36(4H, m), 7.13 (1H, dd, 8.92 Hz, 1.81 Hz), 4.85 (1H, s), 4.17 (4H, m),1.21 (6H, t, J=7.10 Hz).

Step 5. [6-Chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 1 (method B) from diethyl2-[6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]malonate (step 4).

m.p.: 190-192° C. IR (KBr) ν: 3304, 1709, 1630, 1589, 1526, 1427, 1321,1231, 1150, 1061 cm¹. ¹H-NMR (DMSO-d₆) δ: 11.66 (1H, s), 7.72 (1H, d,J=2.00 Hz), 7.64 (1H, d, 8.91 Hz), 751-7.33 (3H, m), 7.01 (1H, dd,J=2.00, 8.91 Hz), 3.61 (2H, s).

Example 203Methyl[6-chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 4-chloro-3-fluorophenacyl bromide* .

* 4-chloro-3-fluorophenacylbromide was prepared as follows;

¹H-NMR (CDCl₃) δ: 8.87 (1H, br s), 7.65-7.36 (4H, m), 7.17 (1H, dd,J=8.72 Hz, 1.81 Hz), 3.80 (2H, s), 3.68 (3H, s).

4-Acetyl-1-chloro-2-fluorobenzene:

To a solution of 1-bromo-4-chloro-3-fluorobenzene (2.09 g, 10 mmol) indry diethyl ether (12.0 ml) was added a solution of n-BuLi (1.55M inhexane, 6.77ml, 10.5 mmol) at −78° C. under nitrogen atmosphere. Themixture was allowed to warm to −20_C stirred for 45 min. A solution ofN,N-dimethylacetamide (1.04 ml, 11.2 mmol) in diethyl ether (1.5 ml) wasadded and the mixture stirred for an additional 1 h. The mixture wasthen allowed to warm to room temperature. After stirring for 3 h, thereaction mixture was poured into saturated aqueous ammonium chloride (20ml) and extracted with diethyl ether (30 ml×3). The combined organiclayers were washed with 2N aqueous HCl (20 ml), saturated aqueous sodiumbicarbonate (20 ml), brine (20 ml), and dried (MgSO₄). Removal ofsolvent gave the title compound as a yellow oil (quant.).

¹H-NMR (CDCl₃) δ: 7.75-7.09 (3H, m), 2.59 (3H, s).

4-Chloro-3-fluorophenacyl Bromide:

The title compound was prepared from 4-acetyl-1-chloro-2-fluorobenzeneaccording to the procedure for preparing 4-(trifluoromethoxy)phenacylbromide described in Example 189.

¹H-NMR (CDCl₃) δ: 7.79-7.71 (2H, m), 7.58-7.52 (1H, m), 4.38 (2H, s).

Example 204 [6-Chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-(4-methylsulfonylaminophenacyl)-1H-indol-3-yl]acetate(Example 203).

m.p.: 179-182° C. MS (EI) m/z: 365 (M⁺). ¹H-NMR (DMSO-d₆) δ: 11.80 (1H,br s), 7.85-7.48 (5H, m), 7.14 (1H, dd, J=8.72 Hz, 1.97 Hz), 3.84 (2H,s).

Example 205 Methyl[6-chloro-2-(4-cyanobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 8 (Method B) from methyltrans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8,Method A) and 4-cyanophenacyl bromide.

¹H-NMR (CDCl₃) δ: 8.88 (1H, br s), 7.89-7.80 (4H, m), 7.58 (1H, d,J=8.75 Hz), 7.41 (1H, d, 1.65 Hz), 7.18 (1H, dd, 8.75 Hz, 1.65 Hz), 3.74(2H, s), 3.36 (3H, s).

Example 206 Methyl[6-chloro-2-[4-(bromo)benzoyl-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 4-bromophenacyl bromide.

¹H-NMR (CDCl₃) δ: 8.89 (1H, br s), 7.66 (4H, s), 7.55 (1H, d, J=8.6 Hz),7.36 (1H, d, J=1.6 Hz), 7.15 (1H, dd, J=8.6, 1.6 Hz), 3.81 (2H, s), 3.66(3H, s).

Example 207Methyl[6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetate

A mixture of methyl[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate(Example 206, 0.40 g, 0.98 mmol), thiophene-2-boronic acid (0.14 g, 1.08mmol), saturated aqueous sodium bicarbonate (4 ml), anddichlorobis(triphenylphosphine)palladium(II) (70 mg, 0.098 mmol) in DME(15 ml) was refluxed for 3 h. The mixture was poured into water (30 ml),and extracted with ethyl acetate (50 ml×2). The combined extracts werewashed with brine (50 ml), dried (MgSO₄), and concentrated. The residuewas purified by flash column chromatography eluting with ethylacetate-hexane (1:6) to afford 0.33 g (83%) of the title compound asyellow solids.

¹H-NMR (CDCl₃) δ: 8.88 (1H, br s), 7.83 (2H, d, J=8.2 Hz), 7.75 (2H, d,J=8.2 Hz), 7.58 (1H, d, J=8.6 Hz), 7.46 (1H, dd, J=3.6, 1.2 Hz),7.42-7.38 (2H, m), 7.19-7.12 (2H, m), 3.87 (2H, s), 3.67 (3H, s).

Example 208 [6-Chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetate (Example207).

m.p.: 246-249° C. IR (KBr) ν: 3319, 3068, 2628, 1705, 1610, 1593, 1427,1323, 1257, 1186, 941 cm¹. ¹H-NMR (DMSO-d₆) δ: 11.79 (1H, s), 7.87 (2H,d, J=8.6 Hz), 7.82 (2H, d, J=8.6 Hz), 7.77-7.68 (3H, m), 7.48 (1H, d,J=1.5 Hz), 7.26-7.20 (1H, m), 7.13 (1H, dd, J=8.6, 2.0 Hz), 3.86 (2H,s).

Example 209 Methyl[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 207 frommethyl[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (Example 206)and furan-2-boronic acid.

¹H-NMR (CDCl₃) δ: 8.90 (1H, br s), 7.83 (2H, d, J=8.7 Hz), 7.80 (2H, d,J=8.7 Hz), 7.60-7.54 (2H, m), 7.40 (1H, d, J=1.8Hz), 7.15 (1H, dd,J=8.6, 1.8 Hz), 6.83 (1H, d, J=3.5 Hz), 6.57-6.52 (1H, m), 3.86 (2H, s),3.66 (3H, s).

Example 210 [6-Chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate (Example209).

m.p.: 230-232° C. IR (KBr) ν: 3315, 2873, 2630, 1709, 1616, 1597, 1527,1431, 1321, 1257, 1232 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.80 (1H, s),7.93-7.79 (3H, m), 7.83 (2H, d, J=8.1 Hz), 7.73 (1H, d, J=8.6 Hz), 7.48(1H, d, J=1.8 Hz), 7.21 (1H, d, J=3.5 Hz), 7.14 (1H, dd, J=8.6, 1.8 Hz),6.72-6.66 (1H, m), 3.84 (2H, s).

Example 211Methyl[6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 207 frommethyl[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (Example 206)and pyridine-3-boronic acid.

¹H-NMR (CDCl₃) δ: 8.95 (1H, br s), 8.90 (1H, d, J=2.5 Hz), 8.69-8.65(1H, m), 7.98-7.92 (1H, m), 7.92 (2H, d, J=8.6 Hz), 7.73 (2H, d, J=8.6Hz), 7.59 (1H, d, J=8.7 Hz), 7.48-7.40 (2H, m), 7.17 (1H, dd, J=8.7, 1.8Hz), 3.88 (2H, s), 3.67 (3H, s).

Example 212 [16-Chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetate (Example211).

m.p.: 194.8° C. IR (KBr) ν: 3224, 2960, 1604, 1568, 1527, 1382, 1321,1259, 1004, 920 cm⁻¹. ¹H-NMR (CD₃OD) δ: 8.93-8.89 (1H, m), 8.57 (1H, dd,J=4.8, 1.5 Hz), 8.24-8.17 (1H, m), 7.98 (2H, d, J=8.6 Hz), 7.85 (2H, d,J=8.6 Hz), 7.68 (1H, d, J=8.6 Hz), 7.60-7.53 (1H, m), 7.46-7.42 (1H, m),7.04 (1H, dd, J=8.6, 1.8 Hz), 3.67 (2H, s).

Example 213Methyl[6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetate

To a stirred solution of thiazole (0.11 g, 1.23 mmol) in diethyl ether(4 ml) was added n-BuLi (1.55M in hexane, 0.79ml) at −78° C. undernitrogen atmosphere. After stirring for 30 min., zinc chloride (1.0M indiethyl ether, 3.7 ml, 3.7 mmol) was added, and the mixture stirred at0° C. for 30 min. To the resulting mixture was added palladium catalystprepared in THF (5 ml) by the treatment of a suspension ofdichlorobis(triphenylphosphine)palladium(II) (0.22 g, 0.31 mmol) withn-BuLi (1.55M in hexane, 0.39 ml).Methyl[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (Example 206,0.25 g, 0.61 mmol) was added to the mixture. The reaction mixture washeated at reflux temperature for 4 h., poured into water (50 ml), andextracted with ethyl acetate (50 ml). The combined extracts were washedwith brine (50 ml), dried (MgSO₄), and concentrated. This crude productwas purified by flash column chromatography eluting with ethylacetate-hexane (1:3) to afford 0.18 g (72%) of the title compound asyellow solids.

¹H-NMR (DMSO-d₆) δ: 11.87 (1H, br s), 8.16 (2H, d, J=8.4 Hz), 8.04 (1H,d, J=3.1 Hz), 7.93 (1H, d, J=3.1 Hz), 7.86 (2H, d, J=8.4 Hz), 7.77 (1H,d, J=8.6 Hz), 7.49 (1H, d, J=1.6 Hz), 7.15 (1H, dd, J=8.6, 1.6 Hz), 3.97(2H, s), 3.54 (3H, s).

Example 214 [6-Chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetate(Example 213).

m.p.: 230-233° C. IR (KBr) ν: 3331, 3126, 2546, 1693, 1635, 1535, 1350,1313, 1213, 1150, 912 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.82 (1H, s), 8.15 (2H,d, J=8.6 Hz), 8.04 (1H, d, J=3.3 Hz), 7.93 (1H, d, J=3.3 Hz), 7.88 (2H,d, J=8.6 Hz), 7.75 (1H, d, J=8.7 Hz), 7.49 (1H, d, J=2.0 Hz), 7.14 (1H,dd, J=8.7, 2.0 Hz), 3.86 (2H, s).

Example 215 Methyl[6-chloro-2-(3-bromobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 3-bromophenacyl bromide.

¹H-NMR (CDCl₃) δ: 8.91 (1H, br s), 7.93-7.87 (1H, m), 7.77-7.67 (2H, m),7.57 (1H, d, J=8.7 Hz), 7.43-7.35 (2H, m), 7.19-7.13 (1H, m), 3.78 (2H,s), 3.69 (3H, s).

Example 216 Methyl[6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 207 frommethyl[6-chloro-2-(3-bromobenzoyl)-1H-indol-3-yl]acetate (Example 215)and furan-2-boronic acid.

¹H-NMR (CDCl₃) δ: 8.93 (1H, br s), 8.05-8.01 (1H, m), 7.94-7.88 (1H, m),7.68-7.62 (1H, m), 7.60-7.47 (3H, m), 7.45-7.41 (1H, m), 7.16 (1H, dd,J=8.6, 1.6 Hz), 6.74 (1H, d, J=3.3 Hz), 6.52-6.47 (1H, m), 3.80 (2H, s),3.57 (3H, s).

Example 217 [6-Chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure describedExample 9 (Method B) frommethyl[6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetate (Example216).

m.p.: 246-249° C. IR (KBr) ν: 3310, 2984, 2632, 1695, 1624, 1568, 1327,1227, 1062, 806, 739 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.81 (1H, s), 8.05-7.96(2H, m), 7.82-7.77 (1H, m), 7.74 (1H, d, J=8.7 Hz), 7.68-7.61 (2H, m),7.49 (1H, d, J=2.0 Hz), 7.14 (1H, dd, J=8.7, 2.0Hz), 7.09 (1H, d, J=3.3Hz), 6.66-6.61 (1H, m), 3.83 (2H, s).

Example 218 Methyldl-2-[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]propionate

Step 1.Methyl[-tert-butoxycarbonyl-2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate

To a stirred suspension ofmethyl[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate (Example 8,Method B, 2.0 g, 5.5 mmol) in dichloromethane (20 ml) was addeddi-tert-butyl dicarbonate (2.4 g, 11 mmol) and 4-dimethylaminopyridine(670 mg, 5.5 mmol) at room temperature. After stirring for 5 min, themixture was poured into 10% citric acid (200 ml) and extracted withdichloromethane (200 ml). The extract was washed with water (200 ml),brine (200 ml), dried (MgSO₄), and concentrated. The residue waspurified by flash column chromatography eluting with ethylacetate-hexane (1:4) to afford 2.3 g (90%) of the title compound as ayellow solids.

¹H-NMR (CDCl₃) δ: 8.26 (1H, d, J=2.2 Hz), 7.74 (2H, d, J=8.6 Hz), 7.53(1H, d, J=8.6 Hz), 7.44 (2H, d, J=8.6 Hz), 7.32 (1H, dd, J=1.6, 8.4 Hz),3.72 (2H, s), 3.56 (3H, s), 1.30 (9H, s).

Step 2.Methyl[1-tert-butoxycarbonyl-2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]propionate

To a stirred solution ofmethyl[1-tert-butoxycarbonyl-2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate(step 1, 200 mg, 0.43 mmol) in THF (3 ml) was added a solution oflithium bis(trimethylsilyl)amide in THF (1 M, 0.5 ml) at −78° C. Afterstirring for 0.5 h, iodomethane (0.14 ml, 2.2 mmol) was added at thattemperature. The mixture was allowed to warm to −10° C. and stirred foran additional 0.5 h. The resulting mixture was poured into saturatedaqueous ammonium chloride (50 ml) and extracted with diethyl ether (50ml). The extract was washed with water (50 ml), brine (50 ml), dried(MgSO₄) and concentrated. The residue was purified by TLC developingwith ethyl acetate-hexane (1:4) to afford 146 mg (71%) of the titlecompound as a colorless oil.

¹H-NMR (CDCl₃) δ: 8.28 (1H, d, J=1.9 Hz), 7.75 (2H, d, J=8.4 Hz), 7.59(1H, d, J=8.4 Hz), 7.44 (2H, d, J=8.6 Hz), 7.28 (1H, dd, J=1.9, 8.4 Hz),3.86 (1H, q, J=7.3 Hz), 3.54 (3H, s), 1.54 (3H, d, J=7.3 Hz), 1.30 (9H,s).

Step 3. Methyl dl-[2-(4-Chlorobenzoyl)-6-methyl-1H-indol-3-yl]propionate

Methyl[1-tert-butoxycarbonyl-2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]propionate(step 2, 270 mg, 0.72 mmol) was dissolved in trifluoroacetic acid (5ml). After siring for 10 min, the mixture was concentrated. To theresidue was added saturated sodium bicarbonate (30 ml), and then themixture was extracted with ethyl acetate (100 ml). The extract waswashed with water (50 ml) brine (50 ml), dried (MgSO₄), andconcentrated. The residue was purified by flash column chromatographyeluting with ethyl acetate-hexane (1:3) to afford 210 mg (78%) of yellowsolids.

¹H-NMR (CDCl₃) δ: 8.89 (1H, br), 7.78 (2H, d, J=8.7 Hz), 7.67 (1H, d,J=8.7 Hz), 7.50 (2H, d, J=8.6 Hz), 7.40-7.37 (1H, m), 7.11 (1H, dd,J=1.8, 8.7 Hz), 4.20 (1H, q, J=7.2 Hz), 3.64 (3H, s), 1.54 (3H, d, J=7.2Hz).

Example 219 dl-2-[2-(4-Chlorobenzoyl)-6-chloro-1H-indol-3-yl]proprionicAcid

The title compound was prepared according to the procedure described inExample 9 (Method B) from methyldl-[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]propionate (Example 218).

¹H-NMR (CDCl₃) δ: 8.77 (1H, br s), 7.82 (2H, d, J=8.6 Hz), 7.75 (1H, d,J=8.7 Hz), 7.53 (2H, d, J=8.6 Hz), 7.40 (1H, br), 7.13 (1H, dd, J=1.8,8.7 Hz), 4.29 (1H, q, J=7.2 Hz), 1.61 (3H, d, J=7.2 Hz).

Example 220Methyl[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl)acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 3-bromoacetylisoquinoline hydrobromide*.

* 3-Bromoacetylisoquinoline hydrobromide was prepared from3-acetylisoquinoline (D. L. Klayman et al., Arzneim. Forsch., 1986, 36,10) according to the method of H. McKennis, Jr., L. B. Turnbull, E. R.Bowman, and E. Tamaki (in J. Org. Chem., 1963, 28, 383-387).

¹H-NMR (CDCl₃) δ: 12.72 (1H, br s), 9.37 (1H, s), 8.80 (1H, s),8.15-8.02 (2H, m), 7.87-7.76 (2H, m), 7.69 (1H, d, J=2.0 Hz), 7.48 (1H,d, J=8.9 Hz), 7.32 (1H, dd, J=2.0, 8.7 Hz), 4.33 (2H, s), 3.76 (3H, s).¹H-NMR (DMSO-d₆) δ: 9.49 (1H, s), 8.68 (1H, s), 8.34-8.26 (2H, m),7.99-7.88 (2H, m), 5.14 (2H, s).

Example 221 [5-Chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate(Example 219).

MS (EI) m/z: 364 (M⁺). m.p.: 239-240° C. IR (KBr) ν: 3277, 1699, 1641,1531, 1329, 1202, 1059, 961, 787 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.46 (1H, brs), 9.56 (1H, s), 8.69 (1H, s), 8.39-8.26 (2H, m), 7.99-7.90 (2H, m),7.87 (1H, d, J=2.1 Hz), 7.72 (1H, d, J=8.7 Hz), 7.35 (1H, dd, J=2.1, 8.9Hz), 4.13 (2H, s).

Example 222Methyl[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 3-bromoacetylisoquinoline(Preparation is described in Example 220).

¹H-NMR (CDCl₃) δ: 12.69 (1H, br s), 9.38 (1H, s), 8.81 (1H, s),8.16-8.04 (2H, m), 7.88-7.77 (2H, m), 7.65 (1H, d, J=8.9 Hz), 7.57 (1H,d, J=2.0 Hz), 7.15 (1H, dd, J=2.0 and 8.7 Hz), 4.36 (2H, s), 3.75 (3H,s).

Example 223 [6-Chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate(Example 222).

MS (EI) m/z: 364 (M⁺). m.p.: 236-237° C. IR (KBr) ν: 3229, 1709, 1641,1618, 1531, 1198, 793 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.43 (1H, br s), 9.56(1H, s), 8.70 (1H, s), 8.41-8.26 (2H, m), 7.99-7.87 (2H, m), 7.82 (1H,d, J=8.7 Hz), 7.77 (1H, d, J=1.5 Hz), 7.14 (1H, dd, J=2.0, 8.6 Hz), 4.14(2H, s).

Example 224Methyl[5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 3-bromoacetyl-5-methylisoxazole (M. D. Amici etal., J. Org. Chem., 1989, 54, 2646).

¹H-NMR (CDCl₃) δ: 10.75 (1H, br s), 7.68 (1H, br s), 7.42 (1H, d, J=8.2Hz), 7.34 (1H, dd, J=1.8, 9.1 Hz), 6.60 (1H, s), 4.25 (2H, s), 3.74 (3H,s), 2.56 (3H, s).

Example 225[5-Chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate(Example 224).

MS (EI) m/z: 318 (M⁺). m.p.: 253-255° C. IR (KBr) ν: 3379, 1699, 1639,1539, 1425, 1259, 1207, 1059, 804 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.76 (1H,br s), 7.81 (1H, d, J=2.0 Hz), 7.59 (1H, d, J=8.9 Hz), 7.29 (1H, dd,J=2.0, 8.7 Hz), 6.67 (1H, s), 4.00 (2H, s), 2.49 (3H, s).

Example 226Methyl[6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 3-bromoacetyl-5-methylisoxazole (M.D. Amici et al., J. Org. Chem., 1989, 54, 2646).

¹H-NMR (CDCl₃) δ: 10.70 (1H, br s), 7.62 (1H, d, J=8.7 Hz), 7.49 (1H, d,J=1.8 Hz), 7.15 (1H, dd, J=1.8 and 8.7 Hz), 6.60 (1H, br s), 4.27 (2H,s), 3.72 (3H, s), 2.56 (3H, s).

Example 227[6-Chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate(Example 226).

MS (EI) m/z: 318 (M⁺). m.p.: 227-229° C. IR (KBr) ν: 3331, 1713, 1645,1543, 1404, 1259, 1202, 891, 804 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.70 (1H, brs), 7.74 (1H, d, J=8.7 Hz), 7.62 (1H, d, J=1.3 Hz), 7.07 (1H, dd, J=1.8,8.6 Hz), 6.67 (1H, br s), 4.01 (2H, s), 2.49 (3H, s).

Example 228Methyl[5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 5-bromoacetyl-4-methyl-1,2,3-thiadiazolehydrobromide*.

* 5-Bromoacetyl-4-methyl-1,2,3-thiadiazole hydrobromide was prepared asfollows;

¹H-NMR (CDCl₃) δ: 9.00 (1H, br s), 7.63 (1H, br s), 7.34 (1H, dd, J=1.8,8.9 Hz), 7.28 (1H, d. J=8.9 Hz), 3.81 (2H, s), 3.66 (3H, s), 2.78 (3H,s).

N-Methoxy-N-methyl-4-methyl-1,2,3-thiadiazole-5-carboxamide:

To a solution of 1,2,3-thiadiazole-5-carbonyl chloride (10.00 g, 61.5mmol) and N,O-dimethylhydroxylamine hydrochloride (7.20 g, 73.8 mmol) indichloromethane (200 ml) was added triethylamine (20.6 ml, 147.6 mmol)at 0° C. After stirring for 2 h at room temperature, the mixture wasdiluted with dichloromethane (300 ml), washed with water (200 ml×2) anddried (MgSO₄). Removal of solvent gave 11.31 g (98%) of the titlecompound as brown crystals.

¹H-NMR (CDCl₃) δ: 3.75 (3H, s), 3.40 (3H, s), 3.01 (3H, s),

5-Acetyl-4-methyl-1,2,3-thiadiazole:

To a solution ofN-methoxy-N-methyl-4-methyl-1,2,3-thiadiazole-5-carboxamide (11.31 g,60.4 mmol) in THF (100 ml) was added 2M diethyl ether solution ofmethylmagnesium iodide (45.3 ml, 90.6 mmol) over 0.5 h at 0° C. Themixture was allowed to warm to room temperature and stirred for 3 h. Themixture was quenched with saturated aqueous ammonium chloride (100 ml)and then extracted with diethyl ether (200 ml×2). The extracts weredried (MgSO₄) and concentrated to give 7.49 g (87%) of the titlecompound as a pale brown oil.

¹H-NMR (CDCl₃) δ: 2.96 (3H, s), 2.67 (3H, s).

5-Bromoacetyl-4-methyl-1,2,3-thiadiazole:

To a solution of 5-acetyl-4-methyl-1,2,3-thiadiazole (1.00 g, 7.03 mmol)in chloroform (20 ml) was added dropwise a solution of bromine (1.24 g,7.73 mmol) in chloroform (10 ml) over 0.5 h at room temperature. Themixture was heated at reflux temperature for 2 h. After cooling to roomtemperature, the mixture was made basic with saturated aqueous sodiumbicarbonate and extracted with dichloromethane (100 ml×2). The extractswere dried (Na₂SO₄) and concentrated to give 1.55 g (100%) of the titlecompound as a brown oil.

¹H-NMR (CDCl₃) δ: 4.28 (2H, s), 2.98 (3H, s).

Example 229[5-Chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]aceticAcid

A mixture ofmethyl[5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate(Example 228, 190 mg, 0.54 mmol), 2N aqueous HCl (4 ml), and acetic acid(20 ml) was heated at reflux temperature for 2 h. After cooling to roomtemperature, the mixture was concentrated. The crystalline residue wasdiluted with THF (100 ml) and dried (MgSO₄) and concentrated. Theresidual solids were washed with ethyl acetate gave 145 mg (79%) of thetitle compound as yellow solids.

MS (EI) m/z: 335 (M⁺). m.p.: 229-230° C. IR (KBr) ν: 3300, 1715, 1622,1526, 1329, 1261, 1204, 1063, 1009, 822 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.92(1H, br s), 7.89 (1H, d, J=2.0 Hz), 7.48 (1H, d, J=8.9 Hz), 7.36 (1H,dd, J=2.0, 8.9 Hz), 3.95 (2H, s), 2.63 (3H, s).

Example 230Methyl[6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and5-bromoacetyl-4-methyl-1,2,3-thiadiazole (Preparation is described inExample 228).

tlc: Rf=0.56 (ethyl acetate/hexane=1:2).

Example 231[6-Chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 229 frommethyl[6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate(Example 230).

MS (EI) m/z: 335 (M⁺). m.p.: 215-216° C. IR (KBr) ν: 3300, 1709, 1645,1531, 1327, 1211, 1065, 922, 789 cm⁻¹. 1H-NMR (DMSO-d₆) δ: 12.35 (1H, brs), 11.86 (1H, br s), 7.82 (1H, d, J=8.7 Hz), 7.47 (1H, d, J=1.8 Hz),7.17 (1H, dd, J=1.8, 8.6 Hz), 3.93 (2H, s), 2.63 (3H, s).

Example 232Methyl[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-5-methylthiazole hydrobromide*.

* 2-Bromoacetyl-5-methylthiazole was prepared from2-acetyl-5-methylthiazole (Metzger et al., Bull. Soc. Chim. Fr., 1953,702) according to the method of H. McKennis, Jr., L. B. Tumbull, E. R.Bowman, and E. Tamaki (in J. Org. Chem., 1963, 28, 383-387).

¹H-NMR (CDCl₃) δ: 11.74 (1H, br s), 7.76 (1H, d, J=1.1 Hz), 7.67 (1H, d,J=1.8), 7.43 (1H, d, J=8.7 Hz), 7.32 (1H, dd, J=2.0, 8.7 Hz), 4.28 (2H,s), 3.73 (3H, s), 2.62 (3H, d, J=1.0 Hz). ¹H-NMR (DMSO-d₆) δ: 7.91 (1H,d, J=1.2 Hz), 4.87 (2H, s), 2.58 (3H, d, J=0.8 Hz).

Example 233[5-Chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3yl]acetate(Example 232).

MS (EI) m/z: 334 (M⁺). m.p.: 231-233° C. IR (KBr) ν: 3348, 1699, 1630,1541, 1404, 1333, 1271, 1057, 1003, 804 cm¹. ¹H-NMR (DMSO-d₆) δ: 12.05(1H, br s), 8.04 (1H, s), 7.88 (1H, br s), 7.77 (1H, d, J=8.7 Hz), 7.35(1H, br d, J=8.9 Hz), 4.15 (2H, s), 2.63 (3H, s).

Example 234Methyl[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and 2-bromoacetyl-5-methylthiazole(Preparation is described in Example 232).

¹H-NMR (CDCl₃) δ: 11.73 (1H, br s), 7.77 (1H, s), 7.62 (1H, d, J=8.2Hz), 7.51 (1H, br s), 7.14 (1H, br d, J=8.7 Hz), 4.31 (2H, s), 3.72 (3H,s), 2.62 (3H, s).

Example 235[6Chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate(Example 234).

MS (EI) m/z: 334 (M⁺). m.p.: 225-226° C. IR (KBr) ν: 3277, 1707, 1630,1541, 1398, 1350, 1231, 1219, 1138, 878, 800 cm¹. ¹H-NMR (DMSO-d₆) δ:12.25 (1H,. br s), 11.99 (1H, br s), 8.04 (1H, s), 7.82 (1H, s), 7.81(1H, d, J=9.0 Hz), 7.13 (1H, br d, J=8.7 Hz), 4.15 (2H, s), 2.63 (3H,s).

Example 236 [6-Chloro-2-(2-thienyl)carbonylindol-3-yl]acetic Acid

Step 1. 6-Chloro-2-(2-thienylcarbonyl)-1-(phenylsulfonyl)indole

The title compound was prepared according to the procedure described instep 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole(step 1 of Example 2, Method B) and 2-thienoyl chloride.

¹H-NMR (CDCl₃) δ: 8.13-8.16 (3H, m), 7.77-7.80 (2H, m), 7.50-7.63 (4H,m), 7.29 (1H, dd, J=1.8, 8.4 Hz), 7.19 (1H, t, J=5.4 Hz), 7.03 (1H, s).

Step 2. 6-Chloro-2-(2-thienylcarbonyl)indole

The title compound was prepared according to the procedure described instep 3 of Example 2 (Method B) from6-chloro-2-(2-thienylcarbonyl)-1-(phenylsulfonyl)indole (step 1).

¹H-NMR (CDCl₃) δ: 10.96 (1H, br s), 8.01 (1H, dd, J=1.2, 3.8 Hz), 7.73(1H, dd, J=1.2, 4.9 Hz), 7.64 (1H, d, J=8.6 Hz), 7.54-7.55 (1H, m),7.35-7.37 (1H, m), 7.23 (1H, dd, J=3.8, 4.9 Hz), 7.10 (1H, dd, J=1.8,8.6 Hz).

Step 3. Diethylα-Acetoxy-[6-chloro-2-(2-thienylcarbonyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 4 of Example 2 (Method B) from 6-chloro-2-(2-thienylcarbonyl)indole(step 2).

¹H-NMR (CDCl₃) δ: 8.93 (1H, br s), 7.82 (1H, d, J=8.9 Hz), 7.76 (1H, d,J=4.9 Hz), 7.55 (1H, d, J=3.8 Hz), 7.39 (1H, d, J=1.8 Hz), 7.11-7.18(2H, m), 4.16-4.31 (4H, m), 1.87 (3H, s), 1.17-1.32 (6H, m).

Step 4. Diethyl[6-chloro-2-(2-thienylcarbonyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the procedure described instep 5 of Example 2 (Method B) from diethylα-acetoxy[6-chloro-2-(2-thienylcarbonyl)-1H-indol-3-yl]malonate (step3).

¹H-NMR (CDCl₃) δ: 9.27 (1H, br s), 7.71-7.75 (2H, m), 7.60-7.66 (1H, m),7.05-7.17 (3H, m), 5.56 (1H, s), 4.07-4.26 (4H, m), 1.20-1.28 (6H, m).

Step 5. [6-Chloro-2-(2-thienylcarbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described instep 6 of Example 2 (Method B) fromdiethyl[6-chloro-2-(2-thienylcarbonyl)-1H-indol-3-yl]malonate (step 4).

MS (EI) m/z: 319 (M⁺). m.p.: 177-178° C. IR (KBr) ν: 3323, 1701, 1593,1568, 1524, 1435, 1412, 1323, 1258, 1229, 920 cm⁻¹. 1-NMR (DMSO-d₆) δ:12.25 (1H, br s), 11.85 (1H, br s), 8.13 (1H, d, J=4.9 Hz), 7.89 (IRH,d, J=3.6 Hz), 7.74 (1H, d, J=8.7 Hz), 7.51 (1H, d, J=1.8 Hz), 7.34 (1H,t, J=4.8Hz), 7.15 (1H, dd, J=1.8, 8.7 Hz), 3.96 (2H, s).

Example 237Methyl[6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetate

The reaction was carried out according to the procedure described inExample 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and2-chloroacethyl-3-(1-hydroxy-1-methylethyl)furan*.

* 2-Chloroacethyl-3-(1-hydroxy-1-methylethyl)furan was prepared asfollows;

¹H-NMR (CDCl₃) δ: 9.89 (1H, br s), 7.59 (1H, d, J=1.6 Hz), 7.53 (1H, d,J=8.7 Hz), 7.34 (1H, d, J=1.5 Hz), 7.08 (1H, dd, J=1.6, 8.7 Hz), 6.57(1H, d, J=1.8 Hz), 6.39 (1H, br s), 4.22 (2H, s), 3.73 (3H, s), 1.57(6H, s).

To a solution of 2-(3-furyl)-2-propanol (T. M. Bargar et al., J. Med.Chem., 1986, 29, 315., 2.0 g, 15.85 mmol) in THF (100 ml) was added asolution of n-butyllithium in hexane (1.55M, 30.7 ml, 47.55 mmol) at−78° C. After stirring for 1 h, 2-chloro-N-methoxy-N-methylacetamide(6.54 g, 47.55 mmol) was added at 0° C. Saturated aqueous ammoniumchloride (100 ml) was added to the mixture and the organic layer wasseparated. The organic layer was washed with water (100 ml×2) and brine(50 ml) and dried (MgSO₄). After removal of the solvent, the residue waspurified by flash chromatography eluting with ethyl acetate/hexane (1:4)to afford 1.03 g (32%) of the title compound as an oil.

¹H-NMR (CDCl₃) δ: 7.52 (1H, d, J=1.8 Hz), 6.56 (1H, d, J=1.8 Hz), 5.51(1H, s), 4.74 (2H, s), 1.56 (6H, s).

Example 238[6-Chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetate(Example 237).

MS (EI) m/z: 361 (M⁺). m.p.: 229-230° C. IR (KBr) ν: 3270, 2980, 1270,1591, 1564, 1522, 1398, 1302, 1263, 1200, 785 cm¹. ¹H-NMR (DMSO-d₆) δ:11.78 (1H, br s), 7.97 (1H, d, J=1.6 Hz), 7.77 (1H, d,. J=8.6 Hz), 7.56(1H, d, J=1.5 Hz), 7.13 (1H, dd, J=1.8, 8.6 Hz), 6.87 (1H, d, J=1.6 Hz),5.69(1H, br s), 3.96 (2H, s), 1.53 (6H, s).

Example 239Methyl[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and2-chloroacetyl-3-(methoxymethyl)furan*.

* 2-Chloroacetyl-3-(methoxymethyl)furan was prepared from3-(methoxymethyl)furan (N. Greeves et al., Synthesis, 1993, 1109)according to the procedure for preparing2-chloroacethyl-3-(1-hydroxy-1-methylethyl)furan described in Example237.

¹H-NMR (CDCl₃) δ: 9.81 (1H, br s), 7.60 (1H, d, J=1.6 Hz), 7.56 (1H, d,J=8.7 Hz), 7.40 (1H, d, J=1.5 Hz), 7.10 (1H, dd, J=1.8, 8.7 Hz), 6.79(1H, d, J=1.6 Hz), 4.81 (2H, s), 4.26 (2H, s), 3.74 (3H, s), 3.48 (3H,s). ¹H-NMR (CDCl₃) δ: 7.52 (1H, d, J=1.8 Hz), 6.74 (1H, d, J=1.8 Hz),4.73 (2H, s), 4.62 (2H, s), 3.44 (3H, s).

Example 240 [6-Chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(3-methoxymethyl-2-furoyl)-1H-indol-3-yl]acetate(Example 239).

MS (EI) m/z: 347 (M⁺). m.p.: 212-213° C. IR (KBr) ν: 3373, 3221, 1720,1601, 1576, 1529, 1205, 1173, 1115, 1088 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.72(1H, br s), 8.04 (1H, d, J=1.6 Hz), 7.76 (1H, d, J=8.7 Hz), 7.59 (1H, d,J=1.5 Hz), 7.12 (1H, dd, J=1.8, 8.7 Hz), 6.86 (1H, d, J=1.6 Hz), 4.70(2H, s), 4.02 (2H, s), 3.36 (3H, s).

Example 241[6-Chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic Acid

Step 1.Methyl[6-chloro-1-ethoxycarbonyl-2-(1-methylimidazole-2-carbonyl)indolin-3-yl]acetate

The title compound was prepared according to the procedure described instep 2 of Example 31 from methyltrans-4-chloro-2-(ethoxycarbonylamino)cinnamate (Example 31, step 1) and2-bromoacetyl-1-methylimidazole hydrobromide*.

* 2-bromoacetyl-1-methylimidazole hydrobromide was prepared from2-acetyl-1-methylimidazole according to the procedure for preparing2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 ofExample 31.

MS (EI) m/z: 405 (M⁺). ¹H-NMR (DMSO-d₆) δ: 7.69 (1H, s), 7.27 (1H, s),4.68 (2H, s), 3.81 (3H, s).

Step 2.[6-Chloro-1-ethoxycarbonyl-2-(1-methylimidazole-2-carbonyl)indol-3-yl]aceticacid

The title compound was prepared according to the procedure described instep 3 of Example 31 frommethyl[6-chloro-1-ethoxycarbonyl-2-(1-methylimidazole-2-carbonyl)indolin-3-yl]acetate(step 1).

m.p.: 235.5° C. IR (KBr) ν: 3238, 1695, 1630, 1538, 1402, 1229, 1146cm⁻¹. ¹H-NMR (CDCl₃) δ: 12.3 (1H, br s), 7.64 (1H, d, J=8.7 Hz), 7.50(1H, d, J=1.8 Hz), 7.41 (1H, s), 7.16 (1H, s), 7.09 (1H, dd, J=1.8, 8.6Hz), 4.25 (2H, s), 4.13 (3H, s).

Example 242Methyl[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetate

To a stirred solution of[6-chloro-2-(1-methylimidazole-2-carbonyl)indol-3-yl]acetic acid(Example 241, 65 mg, 0.21 mmol) in methanol (10 ml) was added(trimethylsilyl)diazomethane (1.0 M solution in hexanes, 1.05 ml, 2.1mmol) at room temperature. After stirring for 19 h, the mixture wasconcentrated. The residue was purified by TLC developing with ethylacetate-hexane (1:2) to afford 20 mg (23%) of the title compound asyellow solids.

¹H-NMR (CDCl₃) δ: 12.35 (1H, br s), 7.59 (1H, d, J=8.0 Hz), 7.49 (1H, d,J=1.5 Hz), 7.24 (1H, s), 7.11 (1H, dd, J=1.7, 8.1 Hz), 7.08 (1H, s),4.30 (2H, s), 4.12 (3H, s), 3.71 (3H, s).

Example 243Methyl[5-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-1-methylimidazole hydrobromide(Preparation is described in Example 241).

¹H-NMR (DMSO-d₆) δ: 12.28 (1H, br s), 7.85 (1H, s), 7.77 (1H, d, J=8.7Hz), 7.66 (1H, s), 7.33-7.29 (2H, m), 4.21 (2H, s), 4.03 (3H, s), 3.60(3H, s).

Example 244[5-Chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-yl]acetate(Example 243).

m.p.: 230-233° C. ¹H-NMR (DMSO-d₆) d: 12.50 (1H, br s), 7.84 (1H, s),7.76 (1H, d, J=13.2 Hz), 7.66 (1H, s), 7.35-7.7.28 (2H, m), 4.15 (2H,s), 4.06 (3H, s).

Example 245Methyl[5-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate

Step 1.Methyl[5-chloro-2-[]-[2-(trimethylsilyl)ethoxymethyl]imidazole-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and2-chloroacetyl-l-[2-(trimethylsilyl)ethoxymethyl]imidazole.*

* 2-chloroacetyl-1-[2-(trimethylsilyl)ethoxymethyl]imidazole wasprepared as follows;

¹H-NMR (CDCl₃) d: 12.38 (1H, br s), 7.66 (1H, s), 7.46-7.38 (2H, m),7.34-7.29 (2H, m), 5.95 (2H, s), 4.29 (2H, s), 3.73 (3H, s), 3.66 (2H,t, J=8.0 Hz), 0.98 (2H, t, J=8.0 Hz), 0.03 (9H, s).

To a stirred solution of 1-[2-(trimethylsilyl)ethoxymethyl]imidazole(Jeffrey P. Whitten et al., J. Org. Chem., 51, 1891 (1986), 3.0 g, 15mmol) in THF (30 ml) was added dropwise n-BuLi (1.55 M in n-hexane, 11.0ml, 17 mmol) at −78° C. and the mixture was stirred for 1 h. To theresulting mixture was added 2-chloro-N-methoxy-N-methylacetamide (2.4 g,17 mmol) at that temperature. The mixture was allowed to warm to 0° C.and stirred at for an additional 2 h. The mixture was poured into water(50 ml) and extracted with ethyl acetate (80 ml), dried (MgSO₄) andconcentrated. The residual brown oil was purified by flash columnchromatography eluting with ethyl acetate/hexane (1:4) to afford 1.2 g(32%) of the title compound as a yellow oil.

¹H-NMR (CDCl₃) d: 7.39 (1H, s), 7.25 (1H, s), 5.81 (2H, s), 4.96 (2H,s), 3.60 (2H, t, J=8.2 Hz), 0.95 (2H, t, J=8.2 Hz), 0.02 (9H, s).

Step 2. Methyl[5-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate

To a solution ofmethyl[5-chloro-2-[1-[2-(trimethylsilyl)ethoxymethyl]imidazole-2-carbonyl]-1H-indol-3-yl]acetate(step 1, 300 mg, 0.67 mmol) in methanol (10 ml) was added 2N aqueous HCl(7 ml) and the mixture was refluxed for 1.5 h. After cooling to roomtemperature, the mixture was concentrated. To the residue was addedsaturated aqueous sodium bicarbonate (10 ml ) and then the mixture wasconcentrated. The residual yellow solids were dissolved in THF (100 ml)and dried (MgSO₄). Removal of solvent afforded 220 mg (100%) of thetitle compound as yellow solids.

¹H-NMR (CDCl₃) d: 12.16 (1H, br s), 10.80 (1H, br s), 7.68 (1H, s),7.50-7.28 (5H, m), 4.29 (2H, s), 3.70 (3H, s).

Example 246 [5-Chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate (Example245).

m.p.: 253-254° C. ¹H-NMR (DMSO-d₆) δ: 12.28 (1H, br s), 7.84 (1H, d,J=2.0 Hz), 7.80 (1H, d, J=9.1 Hz), 7.32 (1H, dd, J=2.0, 9.1 Hz), 4.17(2H, s).

Example 247Methyl[6-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate

Step 1.Methyl[6-chloro-2-[1-[2-(trimethylsilyl)ethoxymethyl]imidazole-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(Step 1 of Example 8, Method A) and2-chloroacetyl-1-[2-(trimethylsilyl)ethoxymethyl]imidazole (Preparationis described in step 1 of Example 245).

¹H-NMR (CDCl₃) δ: 12.34, (1H, br s), 7.61 (1H, d, J=8.6 Hz), 7.52 (1H,d, J=1.6 Hz), 7.40 (1H, d, J=1.4 Hz), 7.31 (1H, d, J=1.4 Hz), 7.13 (1H,dd, J=1.6, 8.6 Hz), 5.95 (2H, s), 4.32 (2H, s), 3.72 (3H, s), 3.67 (2H,t, J=8.0 Hz), 1.00 (2H, t, J=8.0 Hz), 0.02 (9H, s).

Step 2. Methyl[5-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described instep 2 of Example 245 frommethyl[6-chloro-2-[1-[2-(trimethylsilyl)ethoxymethyl]imidazole-2-carbonyl]-1H-indol-3-yl]acetate(step 1).

¹H-NMR (CDCl₃) δ: 12.50 (1H, br s), 7.68-7.48 (2H, m), 7.40-7.30 (1H,m), 7.19-7.06 (1H, m), 6.97-6.92 (1H, m), 4.30 (2H, s), 3.67 (3H, s).

Example 248 [6-Chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate (Example247).

m.p.: 252-253° C. ¹H-NMR (DMSO-d₆) δ: 13.63 (1H, br s), 12.40-12.15 (2H,br), 7.88 (1H, d, J=1.8 Hz), 7.78 (1H, d, J=8.6 Hz), 7.59 (1H, s), 7.40(1H, s), 7.11 (1H dd, J=1.8, 8.6 Hz), 4.18 (2H, s).

Example 249Methyl[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 2-bromoacetyl-4-methylthiazole hydrobromide(Cowden, William B. et al., Aust. J. Chem., 1985, 38, 1257).

¹H-NMR (DMSO-d₆) δ: 12.02 (1H, br s), 7.93-7.85 (2H, m), 7.75 (1H, d,J=8.9 Hz), 7.38 (1H, dd, J=2.0, 8.9 Hz), 4.23 (2H, s), 3.60 (3H, s),2.61 (3H, s).

Example 250[5-Chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate(Example 249).

m.p.: 218-220° C. ¹H-NMR (DMSO-d₆) δ: 11.97 (1H, br s), 7.89 (1H, d,J=2.0 Hz), 7.75 (1H, d, J=8.7 Hz), 7.37 (1H, dd, J=2.0, 8.7 Hz), 4.13(2H, s), 2.62 (3H, s).

Example 251Methyl[5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 8 (Method B) from methyltrans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and2-chloroacetyl-1-methylpyrrole (P. D. Croce et al., Synthesis, 1990,212).

¹H-NMR (DMSO-d₆) δ: 11.8 (1H, br s), 7.80 (1H, br s), 7.55 (1H, d, J=8.6Hz), 7.40-7.32 (2H, m), 6.95-6.90 (1H, m), 6.35-6.26 (1H, m), 4.00 (2H,s), 3.43 (3H, s), 2.50 (3H, s).

Example 252[5-Chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetic Acid

A mixture ofmethyl[5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetate(Example 251, 250 mg, 0.79 mmol) and potassium carbonate (900 mg, 6.4mmol) in methanol-water (1:1, 40 ml) was heated at reflux temperaturefor 1 h. After cooling to room temperature, the mixture wasconcentrated. The residue was neutralized with 2N aqueous HCl andextracted with ethyl acetate (50 ml×2) The combined extracts were dried(MgSO₄) and concentrated. The residual solids were recrystallized fromethyl acetate/hexane to afford 40 mg (23%) of the title compound as paleyellow solids.

mp: 203-205° C. ¹H-NMR (DMSO-d₆) δ: 11.56 (1H, br s), 7.57 (1H, s), 7.33(1H, d, J=8.6 Hz), 7.20-7.10 (2H, m), 6.72 (1H, s), 6.10 (1H, s), 3.81(2H, s), 2.52 (3H, s).

Example 253Methyl[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 8 (Method B) from methyltrans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and4-bromoacetyl-2-methylimidazole (Deady, Leslie W. et al., Aust. J.Chem., 1981, 34, 1295).

¹H-NMR (DMSO-d₆) δ: 12.04 (1H br s), 8.51 (1H, s), 7.86 (1H, d, J=2.0Hz), 7.71 (1H, d, J=8.9 Hz), 7.34 (1H, dd, J=2.0, 8.9 Hz), 4.17 (2H, s),3.59 (3H, s), 2.71 (3H, s).

Example 254[5-Chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetate(Example 253).

m.p.: 237-238° C. ¹H-NMR (DMSO-d₆) δ: 12.03 (1H, br), 12.00 (1H, s),8.49 (1H, s), 7.83 (1H, d, J=2.0 Hz), 7.70 (1H, d, J=8.9 Hz), 7.34 (1H,dd, J=2.0, 8.9 Hz), 4.09 (2H, s), 2.87 (3H, s).

Example 255Methyl[5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate(Example 36, step 3) and 5-bromoacetylthiazole hydrobromide*.

* 5-bromoacetylthiazole hydrobromide was prepared from 5-acetylthiazoleaccording to the procedure for preparing 2-bromoacetyl-4-methylpyridinehydrobromide described in step 2 of Example 31.

¹H-NMR (CDCl₃) d: 12.05 (1H, br s), 9.51 (1H, s), 8.62 (1H, s), 7.85(1H, d, J=1.9 Hz), 7.55(1H, d, J=8.7 Hz), 7.35 (1H, dd, J=1.9, 8.7 Hz),4.09(2H, s), 3.59(3H, s). ¹H-NMR (DMSO-d₆) δ: 9.49 (1H, s), 8.34 (1H, s)4.91 (2H, s).

Example 256 [5-Chloro-2-(thiazole-5-carbonyl-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetate (Example255).

m.p.: 175-180° C. ¹H-NMR (DMSO-d₆) δ: 11.80 (1H, br s), 9.48 (1H, s),8.74 (1H, s), 7.78 (1H, s), 7.48 (1H, d, J=8.7 Hz), 7.30 (1H, d, J=8.9Hz), 3.81 (2H, s).

Example 257Methyl[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 8 (Method B) from methyltrans-4-chloro-2-(phenylsulfonylamino)cinnamate (Step 1 of Example 8,Method A) and 2-bromoacetyl-4-methylthiazole hydrobromide (Cowden,William B. et al., Aust. J. Chem., 1985, 38, 1257).

¹H-NMR (DMSO-d₆) δ: 11.95 (1H, br s), 7.90 (1H, s), 7.84 (1H, d, J=8.7Hz), 7.84 (1H, d, J=2.0 Hz), 7.15 (1H, d, J=2.0 Hz), 4.24 (2H, s), 3.60(3H, s), 2.62 (3H, s).

Example 258[6-Chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(4methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate(Example 257).

m.p.: 239-240° C. ¹H-NMR (DMSO-d₆) δ: 11.80 (1H, br s), 7.75 (1H, s),7.68 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=2.0 Hz), 7.02 (1H, dd, J=2.0, 8.4Hz), 4.03 (2H, s), 2.49 (3H, s).

Example 259Methyl[5-chloro-2-[3-(ethoxycarbonyl)isoxazole-5-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 8 (Method B) from methyltrans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) andethyl-5-bromoacetyl)isoxazole-3-carboxylate.

¹H-NMR (DMSO-d₆) δ: 12.07 (1H, br s), 7.93 (1H, d, J=1.9 Hz), 7.70 (1H,s), 7.39 (1H, dd, J=1.9, 12.8 Hz), 7.62 (1H, d, J=12.8 Hz), 4.44 (2H, q,J=7.1 Hz), 4.15 (2H, s), 3.60 (3H, s), 1.37 (3H, t, J=7.1 Hz).

Example 260[5-Chloro-2-[3-(carboxy)isoxazole-5-carbonyl]-1H-indol-3-yl]acetic Acid

To a solution ofmethyl[5-chloro-2-[3-(ethoxycarbonyl)isoxazole-5-carbonyl]-1H-indol-3-yl]acetate(Example 259, 314 mg, 0.80 mmol) in acetic acid (20 ml) was added 2Naqueous HCl (6.0 ml) and the mixture was heated at 110° C. for 5 h. Themixture was then cooled to room temperature and concentrated. Theresidual yellow solids were washed with ethyl acetate and recrystallizedfrom ethyl acetate/hexane to afford 120 mg (43%) of the title compoundas pale yellow solids.

m.p.: 200-205° C. ¹H-NMR (DMSO-d₆) δ: 12.01 (1H, s), 7.91 (1H, s),7.65-7.56 (2H, m), 7.39 (1H, d, J=8.9 Hz), 4.06 (2H, s).

Example 261 Methyl[6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and bromomethyl cyclopropyl ketone*.

*Bromomethylcyclopropyl ketone was prepared from cyclopropyl methylketone according to the procedure for preparing4-(trifluoromethoxy)phenacyl bromide described in Example 189.

¹H-NMR (CDCl₃) δ: 9.55 (1H, br s), 7.58 (1H, d, J=8.56 Hz), 7.26 (1H, d,J=1.97 Hz) 7.10 (1H, dd, J=8.56 Hz, 1.97 Hz), 4.17 (2H, s), 3.73 (3H,s), 2.58-2.49 (1H, m), 1.30-1.25 (2H, m), 1.09-1.02 (2H, m). ¹H-NMR(CDCl₃) δ: 3.91 (2H, s), 2.65 (1H, t, 6.94 Hz), 1.20-0.98 (4H, m).

Example 262 [6-Chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) from methyl2-(6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl)acetate (Example 261).

m.p.: 207-210_° C. IR (KBr) ν: 3304, 3013, 1709, 1624, 1566, 1443, 1414,1387, 1340, 1286, 1248, 1217, 1200, 1157, 1057, 1045, 1022 cm⁻¹. ¹H-NMR(DMSO-d₆) δ: 11.98 (1H, br s), 7.75 (1H, d, J=8.75 Hz), 7.48 (1H, d,J=1.81 Hz) 7.11 (1H, dd, J=8.75 Hz, 1.81 Hz), 4.08 (2H, s), 2.73 (1H,quintet, 6.24 Hz), 1.07 (4H, d, 6.24 Hz).

Example 263 Methyl[6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and bromomethyl cyclobutyl ketone*.

*Bromomethylcyclobutyl ketone was prepared from cyclobutyl methyl ketoneaccording to the procedure for preparing 4-(trifluoromethoxy)phenacylbromide described in Example 189.

¹H-NMR (CDCl₃) δ: 9.35 (1H, br s), 7.53 (1H, d, J=8.72 Hz), 7.18 (1H, d,J=1.65 Hz) 7.07 (1H, dd, J=8.72 Hz, 1.65 Hz), 4.10 (2H, s), 3.77 (3H,s), 3.72 (1H, m), 2.44-1.86 (6H, m). ¹H-NMR (CDCl₃) δ: 3.88 (2H, s),3.60 (1H, m), 2.33-1.80 (6H, m)

Example 264 [6-Chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) from methyl2-(6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl)acetate (Example 263).

m.p.: 225-228° C. IR (KBr) ν: 3303, 2954, 1705, 1632, 1564, 1529, 1437,1412, 1335, 1242, 1213, 1188, 1157, 1056, 1024 cm⁻¹. ¹H-NMR (DMSO-d₆) δ:11.63 (1H, br s), 7.71 (1H, d, J=8.72 Hz), 7.46 (1H, d, J=1.81 Hz), 7.09(1H, dd, J=8.72 Hz, 1.81 Hz), 4.04 (2H, s), 2.30-1.78 (7H, m).

Example 265Methyl[5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-5-tert-butyl-2-(p-toluenesulfonylamino)cinnamate (Example 143,step 2) and 4-chlorophenacyl bromide.

¹H-NMR (CDCl₃) δ: 8.82 (1H, br s), 7,8-7.31 (7H, m), 3.87 (2H, s), 3.67(3H, s), 1.38 (9H, s).

Example 266 [5-(tert-Butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[5-tert-butyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate (Example265).

m.p.: 171° C. IR (KBr) ν: 3241, 2963, 1699, 1634, 1589/1541, 1394, 1331,1222, 1091, 1011 cm⁻¹; ¹H-NMR (DMSO-d₆) δ: 11.48 (1H, br s), 7.78-7.37(7H, m), 3.85 (2H, s), 1.34 (9H, s).

Example 267[6-Chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]-N,N-dimethylacetamide

The title compound was prepared according to the procedure described inExample 43 from[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid(Example 31).

m.p.: 208° C. (decompose). IR (KBr): 3233, 1655, 1638, 1524, 1398, 1200,1134 cm⁻¹. ¹H-NMR (CDCl₃) δ: 12.54 (1H, br s), 8.62 (1H, d, J=5.0 Hz),8.15 (1H, br), 7.79 (1H, d, J=8.7 Hz), 7.49 (1H, d, J=1.8 Hz), 7.40-7.30(1H, m), 7.09 (1H, dd, J=1.8, 8.7 Hz), 4.43 (2H, s), 3.16 (3H, s), 2.98(3H, s), 2.48 (3H, s).

Example 268[6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-methylacetamide

The title compound was prepared according to the procedure described inExample 43 from[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid(Example 31) and methylamine hydrochloride.

m.p.: 231° C. IR (KBr) ν: 3306, 1643, 1595, 1560, 1526, 1277, 1202, 797cm⁻¹. ¹H-NMR (CDCl₃) δ: 12.45 (1H, br), 8.64 (1H, d, J=4.9 Hz), 8.19(1H. br), 7.85 (1H, d, J=8.6 Hz), 7.50 (1H, br), 7.40 (1H, br d, J=4.6Hz), 7.15 (1H, dd, J=1.6, 8.9 Hz), 6.67 (1H, br), 4.14 (2H, s), 2.73(3H, d, J=4.8 Hz), 2.51 (3H, s).

Example 269[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-hydroxyethyl)acetamide

The title compound was prepared according to the procedure described inExample 43 from [5-chloro-2-(4-methylpyridine)-1H-indol-3-yl]acetic acid(Example 36) and 2-aminoethanol.

MS (EI) m/z: 371 (M⁺). m.p.: 195.9° C. ¹H-NMR (DMSO-d₆) δ: 12.28 (1H, brs), 8.69 (1H, d, J=4.9 Hz), 7.94 (1H, br s), 7.78 (2H, m), 7.66 (1H, d,J=8.7 Hz), 7.56 (1H, m), 7.31 (1H, dd, J=2.0 Hz, 8.7 Hz), 3.94 (2H, s),3.09 (2H, dd, J=5.93 Hz, 11.86 Hz), 2.47 (3H, s).

Example 270[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-methoxyacetamide

The title compound was prepared according to the procedure described inExample 43 from [5-chloro-2-(4-methylpyridine)-1H-indol-3-yl]acetic acid(Example 36) and O-mthylhydroxylamine hydrochloride.

MS (EI) m/z: 357 (M⁺). ¹H-NMR (CDCl₃) δ: 12.53 (1H, br s), 9.54 (1H, brs), 8.65 (1H, d, J=5.1 Hz), 8.19 (1H, br s), 7.92 (1H, br s), 7.42 (2H,m), 7.34 (1H, dd, J=1.7 Hz, 8.9 Hz), 4.01 (2H, s), 3.74 (3H, s), 2.52(3H, s).

Example 2712-[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-(1-piperazinyl)-1-ethanone

Step 1.2-[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-(4-tert-butoxycarbonyl-1-piperazinyl)-1-ethanone

The title compound was prepared according to the procedure described inExample 43 from [5-chloro-2-(4-methylpyridine)-1H-indol-3-yl]acetic acid(Example 36) and tert-butyl 1-piperadinecarboxylate.

¹H-NMR (CDCl₃) δ: 12.61 (1H, br s), 8.62 (1H, d, J=5.1 Hz), 8.14 (1H, brs), 7.84 (1H, s), 7.42 (1H, d, J=8.7 Hz), 7.37 (br d, 1H, J=4.9 Hz),7.30 (1H, dd, J=2.0 Hz, 8.9 Hz), 4.42 (2H, s), 3.66 (4H, m), 2.50 (3H,s), 1.64 (4H, m), 1.46 (9H, s).

Step 2.2-[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-(1-piperazinyl)-1-ethanone

To a solution of[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(4-tert-butoxycarbonylpiperadino)acetamide(step 1, 152.6 mg, 0.042 mmol) in THF (1 ml) was added dropwisetrifluoroacetic acid (2 ml) at 0° C. The mixture was stirred at roomtemperature for 1.5 h and then concentrated. The residue was dilutedwith dichloromethane (25 ml), washed with saturated aqueous sodiumbicarbonate (25 ml). The aqueous layer was extracted withdichloromathane (25 ml×2). The combined organic layers were dried(Na₂SO₄) and concentrated. The residue was purified by flash columnchlomatographyon eluting with methanol/dichloromathane (1:10) to afford80.8 mg of the title compound as yellow crystals.

MS (EI) m/z: 396 (M⁺). m.p.:. 205.0° C. IR (KBr) ν: 3244, 1647, 1595,1525, 1429, 1205 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.28 (1H, br s), 8.68 (1H,d, J=4.9 Hz), 7.90 (1H, br s), 7.81 (1H, br s), 7.65 (1H, d, J=8.9 Hz),7.56 (br d, 1H, J=4.1 Hz), 7.31 (1H, dd, J=1.8 Hz, 8.9 Hz), 4.15 (2H, brs), 3.50-3.15 (4H, m), 2.70-2.55 (4H, m), 2.46 (3H, s).

Example 272[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-aminoethyl)acetamide

Step 1.[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-tert-butoxycarbonylaminoethyl)acetamide

The title compound was prepared according to the procedure described inExample 43 from [5-chloro-2-(4-methylpyridine)-1H-indol-3-yl]acetic acid(Example 36) and N-(2-aminoethyl)carbamic acid tert-butyl ester.

¹H-NMR (CDCl₃) δ: 12.29 (1H, br s), 8.68 (1H, d, J=4.9 Hz), 7.94 (1H, brs), 7.78 (2H, m), 7.67 (1H, d, J=8.9 Hz), 7.57 (1H, br d, J=4.9 Hz),7.32 (dd, 1H, J=2.0 Hz, 8.7 Hz), 6.73 (1H, m), 3.94 (2H, s), 3.05-2.95(4H, m), 2.47 (3H, s), 1.35 (9H, s).

Step 2.[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-aminoethyl)acetamide

The title compound was prepared according to the procedure described instep 2 of Example 273 from[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-tert-butoxycarbonylaminoethyl)acetamide(step 1).

MS (EI) m/z: 370 (M⁺). m.p.: 165.7° C. IR (KBr) ν: 3346, 2927, 1665,1627, 1593, 1515, 1435, 1267, 1207 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.28 (1H,br s), 8.69 (1H, d, J=4.9 Hz), 7.93 (1H, br s), 7.80-7.76 (2H, m), 7.66(1H, d, J=8.9 Hz), 7.57 (1H, m), 7.31 (dd, 1H, J=2.0 Hz, 8.9 Hz), 3.94(2H, s), 3.01 (2H, q, J=5.77 Hz), 2.55-2.45 (2H, m), 2.47 (3H, s).

Example 2732-[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl-1-(3-amino-1-pyrrolidinyl)-1-ethanone

Step 1.2-[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-[3-(tert-butoxycarbonylamino)-1-pyrrolidinyl]-1-ethanone

The title compound was prepared according to the procedure described inExample 43 from [5-chloro-2-(4-methylpyridine)-1H-indol-3-yl]acetic acid(Example 36) and 3-(tert-butoxycarbonylamino)pyrrolidine.

¹H-NMR (CDCl₃) δ: 12.56 (1H, br s), 8.62 (1H, d, J=4.9 Hz), 8.18 (1H, brs), 7.78 (1H, br s), 7.42 (1H, d, J=8.9 Hz), 7.35 (1H, br d, J=4.9 Hz),7.29 (2H, m), 4.89 (1H, br d, J=25.05), 4.36-3.45 (7H, m), 2.48 (3H, s),2.35-1.80 (2H, m), 1.46 (9H, s).

Step 2.2-[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-(3-amino-1-pyrrolidinyl)-1-ethanone

The title compound was prepared according to the procedure described instep 2 of Example 271 from2-[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-[3-(tert-butoxycarbonylamino)-1-pyrrolidinyl]-1-ethanone(step 1).

MS (EI) m/z: 396 (M⁺). m.p.: 179.2° C. IR (KBr) ν: 3238, 2876, 1638,1595, 1526, 1423, 1203 cm⁻¹; ¹H-NMR (DMSO-d₆) δ: 12.26 (1H, br s), 8.68(1H, d, J=4.9 Hz), 7.89 (1H, br s), 7.81 (1H, d, J=1.81 Hz), 7.65 (1H,d, J=8.9 Hz), 7.55 (1H, br d, J=5.1 Hz), 7.31 (dd, 1H, J=2.0 Hz, 8.7Hz), 4.07 (1H, s), 4.05 (1H, s), 3.70-2.90 (5H, m), 2.46 (3H, s),2.10-1.80 (1H, m), 1.75-1.45 (1H, m).

Example 274Methyl[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-]acetate

Step 1. Methyl trans-2-Amino-4-chloro-5-fluorocinnamate

The title compound was prepared according to the procedure described instep 1 of Example 133 from 2-bromo-5-chloro-4-fluoroaniline (JP 01311056A2, Nippon Kayaku Co., Ltd., Japan).

¹H-NMR (CDCl₃) δ: 7.69 (1H, d, J=15.8 Hz), 7.15 (1H, d, J=9.7 Hz), 6.74(1H, d, J=6.4 Hz), 6.31 (1H, d, J=15.8 Hz), 3.81 (3H, s).

Step 2. Methyl trans-4-Chloro-5-fluoro-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-2-amino-4-chloro-5-fluorocinnamate (step 1).

¹H-NMR (CDCl₃) δ: 7.71-7.68 (1H, m), 7.57-7.40 (6H, m), 7.23 (1H, d,J=9.4 Hz), 6.09 (1H, d, J=15.8 Hz), 3.77 (3H, s).

Step 3.Methyl[6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-4-chloro-5-fluoro-2-(phenylsulfonylamino)cinnamate (step 2).

¹H-NMR (CDCl₃) δ: 9.05 (1H, br.s), 7.74 (2H, d, J=8.7 Hz), 7.49 (2H, d,J=8.7 Hz), 7.35-7.32 (2H, m), 3.77 (2H, s), 3.66 (3H, s).

Example 275 [6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]AceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate.

m.p.: 215-220° C. IR (KBr) ν: 1709, 1626, 1585, 1529, 1456, 1439, 1279,1250 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.85 (1H, br.s), 7.79-7.75 (3H, m),7.67-7.63 (2H, m), 7.60-7.58 (1H, m), 3.83 (2H, s).

Example 276Methyl[6-chloro-5-fluoro-2-(4-Methylpridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-4-chloro-5-fluoro-2-(phenylsulfonylamino)cinnamate (Example 274,step 2).

¹H-NMR (CDCl₃) δ: 12.54 (1H, br.s), 8.58 (1H, d, J=4.9 Hz), 8.14 (1H,m), 7.56-7.53 (1H, m), 7.39-7.34 (2H, m), 4.25 (2H, s), 3.75 (3H, s),2.48 (3H, s).

Example 277[6-Chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 276).

mp: 219.5° C. IR (KBr) ν: 1732, 1709, 1647, 1597, 1529, 1279, 1252, 1204cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.35 (1H, br.s), 8.70 (1H, d, J=5.1 Hz), 7.96(1H, s), 7.87 (1H, d, J=6.6 Hz), 7.81 (1H, d, J=10.1 Hz), 7.59-7.58 (1H,m), 4.05 (2H, s), 2.47 (3H, s).

Example 278Methyl[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

Step 1.Methyl[6-chloro-2-[4-(1-(tert-buthyldimethylsilyloxy)ethyl]pyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate(step 1 of Example 8, Method A) and2-bromoacetyl-4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine*.

* 2-Bromoacetyl-4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine wasprepared as follows;

¹H-NMR (CDCl₃) δ: 12.49 (1H, br s), 8.71 (1H, d, J=4.9 Hz), 8.24 (1H, d,J=1.5 Hz), 7.61-7.63 (2H, m), 7.53 (1H, d, J=1.8 Hz), 7.13 (1H, dd,J=1.8, 8.7 Hz), 4.96 (1H, q, J=6.4 Hz), 4.32 (2H,s), 3.73 (3H, s), 1.45(3H, d, J=6.4 Hz), 0.93 (9H, s), 0.10 (3H, s), 0.03 (3H, s).

4-[1-(Trimethylsilyoxy)ethyl]-2-pyridinecarbonitrile:

The title compound was prepared from 4-(1-hydroxyethyl)pyridine-N-oxide(C. W. Muth et al., J. Heterocycl. Chem., 1972, 9, 1299) according tothe procedure for preparing 4-chloro-2-pyridinecarbonitrile described inExample 33.

¹H-NMR (CDCl₃) δ: 8.64 (1H, d, J=5.1 Hz), 7.69-7.70 (1H, m), 7.45-7.48(1H, m), 4.88 (2H, q, J=6.4 Hz), 1.43 (3H, d, J=6.6 Hz), 0.14 (9H, s).

4-[1-(tert-Butyldimethylsilyloxy)ethyl]-2-pyridinecarbonitrile:

To a solution of 4-[1-(trimethylsilyloxy)ethyl]-2-pyridinecarbonitrile(39.04 g, 0.1624 mol) in THF (200 ml) was added a solution oftetrabutylammonium fluoride in THF (1M, 178.6 ml, 0.1786 mol) at roomtemperature. After stirring for 0.5 h, the mixture was concentrated. Theresidue was diluted with ethyl acetate (300 ml) and washed with water(200 ml). The aqueous layer was then extracted with dichloromethane (200ml×2). The combined organic layers were dried (MgSO₄) and concentrated.The residual oil was dissolved in DMF (200 ml). To the solution wasadded tert-butyldimethylsilylchloride (36.72 g, 0.2436 mol) andimidazole (22.11 g, 0.3248 mol) at room temperture. After stirring for19 h, diethyl ether (500 ml) and water (200 ml) were added to themixture and the organic layer was separated. The organic layer waswashed with water (100 ml×2), dried (MgSO₄) and concentrated. Theresidue was purified by flash column chromatography eluting with ethylacetate/hexane (1:20) to give 39.23 g (92%) of the title compound as anoil.

¹H-NMR (CDCl₃) δ: 8.64 (1H, d, J=5.1 Hz), 7.67-7.68 (1H, m), 7.46-7.48(1H, m), 4.89 (1H, q, J=6.4 Hz), 1.42 (3H, d, J=6.4 Hz), 0.92 (9H, s),0.10 (6H, s).

2-Acetyl-4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine:

The title compound was prepared from4-[1-(tert-butyldimethylsilyloxy)ethyl]-2-pyridinecarbonitrile accordingto the procedure for preparing 2-acetyl-4-chloropyridine describedExample 33.

¹H-NMR (CDCl₃) δ: 8.62 (1H, d, J=4.9 Hz), 7.95-7.96 (1H, m), 7.49-7.52(1H, m), 4.91 (1H, q, J=6.4 Hz), 2.73 (3H, s), 1.41 (3H, d, J=6.4 Hz),0.91 (9H, s), 0.10 (6H, s).

2-Bromoacety-4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine

The title compound was prepared according to the procedure for preparing2-bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine described inExample 95 from2-acetyl-4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine.

Step 2.Methyl[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate.

The title compound was prepared according to the procedure described instep 2 of Example 95 frommethyl[6-chloro-2-[4-[1-(tert-buthyldimethylsilyloxy)ethyl]pyridine-2-carbonyl]-1H-indol-3-yl]acetate(step 1).

¹H-NMR (DMSO-d₆) δ: 12.34 (1H, br s), 8.77 (1H, d, J=5.1 Hz), 8.11 (1H,s), 7.81 (1H, d, J=8.7 Hz), 7.75 (1H, d, J=1.6 Hz), 7.70 (1H, dd, J=1.2,4.9 Hz), 7.13 (1H, dd, J=1.8, 8.6 Hz), 5.61 (1H, d, J=4.6 Hz), 4.84-4.93(1H, m), 4.17 (2H, s), 3.59 (3H, s), 1.39 (3H, d, J=6.4 Hz).

Example 279[6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 58 frommethyl[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate(Example 278).

m.p.: 193-194° C. IR (KBr) ν: 3464, 1707, 1632, 1591, 1526, 1250, 1225,1192, 1144, 914 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 12.30 (1H, br s), 8.78 (1H, d,J=5.1 Hz), 8.11 (1H, s), 7.79 (1H, d, J=8.6 Hz), 7.74 (1H, d, J=1.6 Hz),7.71 (1H, d, J=5.3 Hz), 7.12 (1H, dd, J=1.8, 8.7 Hz), 5.60 (1H, d, J=4.4Hz), 4.84-4.93 (1H, m), 4.09 (2H, s), 1.39 (3H, d, J=6.6 Hz).

Example 280[6-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1-H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 112 frommethyl[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 113).

m.p.; 193-194° C. IR (KBr) ν: 3256, 1707, 1645, 1529, 1420, 1227, 1180,1159, 1153 cm⁻¹. MS (EI) m/z: 360 (M⁺). ¹H-NMR (DMSO-d₆) δ: 11.84 (1H,br s), 8.46 (1H, d, J=5.3 Hz), 7.77 (1H, d, J=8.7 Hz), 7.67 (1H, t,J=5.1 Hz), 7.51 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=1.8, 8.6 Hz), 3.74(2H, s), 2.76 (2H, q, J=7.6 Hz), 1.25 (3H, t, J=7.6 Hz).

Example 281 [6-Chloro-2-(2-nitrobenzoyl)-1H-indol-3-yl]acetic Acid

Step 1. Polymer-bound trans 4-Chloro-2-(phenylsulfonylamino)cinnamate

To a mixture of Wang resin (200-400 mesh, 1.37 g, ca. 0.89 mmol) andtrans 4-chloro-2-(phenylsulfonylamino)cinnamic acid (600 mg, 1.77 mmol)was added dichloromethane (10 ml) and N,N-diisopropylethylamine (1.86ml, 10.7 mmol). The mixture was allowed to stand for 1h, and then4-dimethylaminopyridine (22 mg, 0.18 mmol) and WSC (339 mg, 1.77 mmol)were added. The mixture was agitated for 18 h and filtrated. Theresidual resin was washed with water (20 ml×3), methanol (20 ml×3),acetone (20 ml×3), dichloromethane (20 ml×3) and dried to give 1.65 g ofthe title compound.

Step 2. [6-Chloro-2-(2-nitrobenzoyl)-1H-indol-3-yl]acetic Acid

To a mixture of polymer-bound trans4-chloro-2-(phenylsulfonylamino)cinnamate (step 1, 100 mg, 53 μmol) and2-nitrophenacyl bromide (39 mg, 0.16 mmol) in acetone (3 ml) was addedpotassium carbonate (37 mg, 0.27 mmol). The mixture was agitated for 18h. and filtrated. The residual resin was washed with water (20 ml×3),acetone (20 ml×3), dichloromethane (20 ml×3) and THF (20 ml×2) anddried. The resin was diluted with THF (4 ml) and then DBU was added (40μl, 0.27 mmol). After agitating for 6 h, the resin was filtered off andwashed with THF (20 ml×3), acetone (20 ml×3) and dichloromethane (20ml×3). To the resin was added 95% trifluoroacetic acid indichloromethane (5 ml) and the mixture was agitated for 3 h. The mixturewas filtered and the residue was washed with dichloromethane (20 ml×5).The filtrate was concentrated and the residue was purified by HPLC(MeOH/AcONH₄ aquous solution=60/40-90/10) to give 3.2 mg (17%) of thetitle compound.

MS (ESI) m/z: 359 (MH⁺).

Example 282 [6-Chloro-2-(2,4-dimethoxybenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 281 from 4-chloro-2-(phenylsulfonylamino)cinnamic acid.

MS (ESI) mn/z: 374 (MH⁺).

Example 283 [6-Chloro-2-(4-difuluoromethoxybenzoyl)-1H-indol-3-yl]aceticAcid

The title compound was prepared according to the procedure described inExample 289 from 4-chloro-2-(phenylsulfonylamino)cinnamic acid.

MS (ESI) m/z: 380 (MH⁺).

Example 284 [6-Chloro-2-(2,5-dimethoxybenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 281 from 4-chloro-2-(phenylsulfonylamino)cinnamic acid.

MS (ESI) m/z: 374 (MH⁺).

Example 285 Methyl[5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

Step 1. 4-Acetyl-2-bromoaniline

To a stirred suspension of 4-acetamido-3-bromoacetophenone in ethanol(12 ml) was added droppwise hydrochloric acid (3 ml) at 0° C. Thereaction mixture was stirred under reflux condition for 4.5 h. Themixture was cooled and concentrated. The residual solids werepartitioned between saturated aqueous sodium bicarbonate (50 ml) anddiethyl ether (50 ml). The aqueous layer was extracted with ethylacetate (50 ml×2). The combined organic layers were dried (MgSO₄) andconcentrated to afford 1.79 g (quant.) of the title compound as a brownoil.

¹H-NMR (CDCl₃) δ: 8.06 (1H, d, 1.97 Hz), 7.76-7.72 (1H, m), 6.74 (1H, d,8.40 Hz), 4.60 (1H, br s), 2.50 (s, 3H).

Step 2. Methyl trans-(5-Acetyl-2-amino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 133 from 4-acetyl-2-bromoaniline (step 1) and methylacrylate.

¹H-NMR (CDCl₃) δ: 8.02 (1H, d, 2.13 Hz), 7.81-7.75 (2H, m), 6.70 (1H, d,8.56 Hz), 6.44 (1H, d, 15.8 Hz), 4.55 (2H, br s), 3.81 (3H, s), 2.53(3H, s).

Step 3. Methyl trans-5-Acetyl-2-(p-toluenesulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-(5-acetyl-2-amino)cinnamate (step 2) and p-toluenesulfonylchloride.

¹H-NMR (CDCl₃) δ: 8.01 (1H, d, 2.00 Hz), 7.89 (1H, dd, 8.59 Hz, 1.97Hz), 7.68-7.22 (7H, m), 6.30 (1H, s), 6.15 (1H, d, 15.8 Hz), 3.81 (3H,s), 2.57 (3H, s), 2.38 (3H, s).

Step 4. Methyl[5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-5-acetyl-3-(p-toluenesulfonylamino)cinnamate (step 3) and4-chiorophenacyl bromide.

¹H-NMR (CDCl₃) δ: 9.2 (1H, br s), 8.34-7.75 (4H, m), 7.52-7.45 (3H, m),3.89 (2H, s), 3.69 (3H, s), 2.68 (3H, s).

Example 286 [5-Acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inMethod B of Example 9 frommethyl[5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate (Example 285).

m.p.: 225° C. IR (KBr) ν: 3281, 1703, 1666, 1643, 1614, 1574, 1539,1452, 1425, 1402, 1364, 1263, 1240, 1178, 1092, 1011, 959 cm⁻¹. ¹H-NMR(DMSO-d₆) δ: 12.01 (1H, br s), 8.49 (1H, br s), 7.93-7.89 (1H, m), 7.78(2H, d, 8.56 Hz), 7.65 (d, 2H, 8.56 Hz), 7.52 (1H, d, 8.72 Hz), 3.93(2H, s), 2.63 (3H, s).

Example 287Methyl[6-fluoro-2-(4-Methylpridine-2-carbonyl)-1H-indol-3-yl]acetate

Step 1. Methyl trans-(4-Fluoro-2-nitro)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 133 from 3-fluoro-6-iodonitrobenzene and methylacrylate.

¹H-NMR (CDCl₃) δ: 8.67 (1H, d, 15.8 Hz), 7.78 (1H, dd, 8.07 Hz, 2.65Hz), 7.68-7.63 (2H, m), 6.34 (1H, d, 15.8 Hz), 3.84 (3H, s).

Step 2. Methyl trans-(2-Amino-4-fluoro)cinnamate

The title compound was prepared according to the procedure described instep 2 of Example 36 from methyl trans-(4-fluoro-2-nitro)cinnamate (step1).

¹H-NMR (CDCl₃) δ: 7.75 (1H, d, 15.8 Hz), 7.37-7.31 (1H, m), 6.50-6.37(2H, m), 6.32-6.26 (1H, m), 4.13 (2H, br s), 3.80 (3H, s).

Step 3. Methyl trans-4-Fluoro-2-(p-toluenesulfonylamino)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 (Method A) from methyltrans-(2-amino-4-fluoro)cinnamate (step 2).

¹H-NMR (CDCl₃) δ: 7.64 (1H, d, 8.40 Hz), 7.46-7.19 (4H, m), 6.94-6.87(1H, m), 6.77 (1H, s), 6.16-6.10 (1H, m), 3.79 (3H, s), 2.38 (3H, s).

Step 4.Methyl[6-fluoro-2-(4-methylpridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-4-fluoro-2-(p-toluenesulfonylamino)cinnamate (step 3).

¹H-NMR (CDCl₃) δ: 12.49 (1H, br s), 8.61 (1H, d, 4.94 Hz), 8.17-7.61(2H, m), 7.36-7.14 (2H, m), 6.98-6.90 (1H, m), 4.31 (2H, s), 3.73 (3H,s), 2.47 (3H, s).

Example 288[6-Fluoro-2-(4-methylpridine-2-carbonyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inExample 9 (Method B) frommethyl[6-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate(Example 287).

m.p.: 208° C. IR (KBr) ν: 3238, 1701, 1638, 1597, 1533, 1398, 1281,1211, 1132, 1003 cm⁻¹. ¹H-NMR (CDCl₃) δ: 12.28 (1H, br s), 8.70 (1H, d,4.94 Hz), 7.96 (1H, s), 7.83-7.77 (1H, m), 7.57 (1H, d, 4.94 Hz), 7.42(1H, dd, 10.2 Hz, 2.13 Hz), 7.03-6.95 (1H, m), 4.09 (2H, s), 2.47 (3H,s).

Example 289 Methyl[6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

The title cornpound was prepared according to the procedure described inExample 57 from methyltrans-4-fluoro-3-(p-toluenesulfonylamino)cinnamate (step 3 of Example287) and 4-chlorophenacylbromide.

¹H-NMR (CDCl₃) δ: 9.10 (1H, br s), 7.76-7.71 (2H, m), 7.60-7.54 (2H, m),7.50-7.45 (2H, m), 7.04-6.90 (2H, m), 3.81 (2H, s), 3.66 (3H, s).

Example 290 [6-Fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the proceduie described inExample 9 (Method B) frommethyl[6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate (Example 289).

m.p.: 214° C. IR (KBr) ν: 3335, 1699, 1618, 1605, 1587, 1531, 1425,1327, 1267, 1231, 1134, 1094, 1001 cm⁻¹. ¹H-NMR (DMSO-d₆) δ: 11.73 (1H,br s), 7.78-7.63 (5H, m), 7.17 (1H, dd, 9.72 Hz, 2.13 Hz), 7.04-6.96(1H, m), 3.84 (2H, s).

Example 291[2-(4-Methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic Acid

Step 1. Methyl trans-(2-Amino-5-methylthio)cinnamate

The title compound was prepared according to the procedure described instep 1 of Example 133 from 2-bromo-4-methylthioxyaniline (JP80-122756)and methyl acrylate.

¹H-NMR (CDCl₃) δ: 7.77 (1H. d, 15.8 Hz), 7.38 (1H, d, 2.13 Hz), 7.19(1H, dd, 8.40 Hz, 2.13 Hz), 6.66 (1H, d, 8.40 Hz), 6.36 (1H, d, 15.8Hz), 3.97 (1H, br s), 3.80 (3H, s), 2.43 (3H, s).

Step 2. Methyl trans-2-p-Toluenesulfonylamino-5-methylthiocinnamate

The title compound was prepared according to the procedure described instep 1 of Example 8 from metbyl trans-(2-amino-4-methylthio)cinnamate(step 1) and p-toluenesulfonyl chloride.

¹H-NMR (CDCl₃) δ: 7.81 (2H, d, 8.40 Hz), 7.56-6.91 (8H, m), 6.13 (1H, d,15.6 Hz), 3.79 (3H, s), 2.46 (3H, s), 2.39 (3H, s).

Step 3.Methyl[2-(4-methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetate

The title compound was prepared according to the procedure described inExample 57 from methyltrans-2-p-toluenesulfonylamino-5-methylthiocinnamate (step 2) and2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described instep 2 of Example 31).

¹H-NMR (CDCl₃) δ: 12.47 (1H, br s), 8.62 (1H, d, 4.78 Hz), 8.19-8.17(1H, m), 7.65-7.62 (1H, m), 7.47-7.30 (3H, m), 4.31 (2H, s), 3.73 (3H,s), 2.48 (3H, s).

Example 292

[2-(4-Methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic Acid

The title compound was prepared according to the procedure described inMethod B of Example 9 frommethyl[2-(4-methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetate(Example).

¹H-NMR (DMSO-d₆) δ: 12.22 (1H, br s), 8.70 (1H, d, 4.62 Hz), 7.95-7.17(4H, m), 4.08 (2H, s), 2.47 (3H, s), 2.35 (3H, s). MS (EI) m/z: 340(M⁺).

Example 293 3-[4-Chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylic AcidEthyl Ester

To 3-(2-amino-4-chloro-phenyl)-acrylic acid ethyl ester (18.0g, 79.8mmol) in dichloromethane (144 ml) was added pyridine (9.04 ml, 112 mmol)and p-toluenesulfonyl chloride (16.0g, 83.9 mmol). The reaction wasstirred at room temperature for 18 hours and poured into 1N hydrochloricacid (150 ml). The layers were separated and the organic layer was driedover magnesium sulfate, filtered, and concentrated. The resulting solidwas slurried in hexanes and filtered to afford3-[4-chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylic acid ethyl ester(28.3g, 93%). mp=124-127° C. ¹H NMR (300 MHz, CDCl₃) d 1.35 (t, 3,J=7.2), 2.40 (s, 3), 4.27 (q, 2, J=7.2), 6.12 (dd, 1, J=15.9, 0.9),7.20-7.39 (m, 4), 7.39 (d, 1, J=8.6), 7.48-7.53 (m, 2), 7.62 (d, 2,J=8.3). ¹³C NMR (75 MHz, CDCl₃) d 15.50, 22.79, 62.24, 122.48, 127.98,128.49, 129.34, 129.50, 131.05, 136.82, 137.00, 137.73, 138.93, 145.55,167.59. IR 3214, 1694, 1631, 1318, 1167 cm⁻¹. Analysis calculated forC₁₈H₁₈ClNO₄S: C, 56.91; H, 4.78; N, 3.69. Found: C, 57.10; H, 5.08; N,3.70.

Example 294 [6-Chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-acetic Acid

To a solution of 3-[4-chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylicacid ethyl ester (13.0g, 34.2 mmol) in N,N-dimethylacetamide (120 ml)was added potassium carbonate (9.45 g, 68.4 mmol) and2-bromo-4′-chloroacetophenone (8.78 g, 37.6 mmol) and the reaction wasstirred at room temperature for 15 minutes. 1N Sodium hydroxide (130 ml)was added and the reaction mixture was heated to 100° C. for 8 hours.The reaction mixture was cooled to room temperature and poured into aseparatory funnel and washed with methyl t-butyl ether (2×200 ml). Theaqueous layer was acidified to pH 1 with 6N hydrochloric acid and wasextracted with ethyl acetate (150 ml). The solvent was removed underreduced pressure and to the resulting oil was added isopropyl alcohol(24 ml) and water (48 ml). A solid precipitated and the slurry wasstirred 12 hours. The precipitate was filtered, washed with water, anddried to provide [6-chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-aceticacid (9.73 g, 82%). mp 181-183° C. ¹H NMR (400 MHz, d₆-DMSO) d 3.79 (s,2), 7.08 (dd, 1, J=8.5, 1.9), 7.42 (d, 1, J=1.9), 7.60 (d, 2, J=8.5),7.62-7.73 (m, 3), 11.74 (bs, 1), 12.22 (bs, 1). ¹³C NMR (75 MHz,d₆-DMSO) d 31.74, 113.25, 118.00, 121.93, 123.96, 127.69, 130.10,131.30, 132.02, 133.59, 138.02, 138.37, 138.58, 173.20, 188.29. IR 3314,1710, 1700, 1618, 1522, 1323, 1227, 1093, 941 cm⁻¹. Analysis calculatedfor C₁₇H₁₁Cl₂NO₃: C, 58.64; H, 3.18; N, 4.02. Found: C, 58.58; H, 3.22;N, 3.93.

Example 2953-{4-Chloro-2-[[2-(4-chloro-phenyl)-2-oxo-ethyl]-(toluene-4-sulfonyl)-amino]-phenyl}-acrylicAcid Ethyl Ester

To a solution of 3-[4-chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylicacid ethyl ester (3.00 g, 7.90 mmol) in NN-dimethylacetamide (15.0 ml)was added potassium carbonate (2.18 g, 15.8 mmol) and2-bromo-4′-chloroacetophenone (2.03 g, 8.69 mmol). The reaction wasstirred for 30 minutes, poured into 1N hydrochloric acid (30 ml) andextracted with methyl f-butyl ether (2×30 ml). The organic extracts weredried over magnesium sulfate, filtered, concentrated to a low volume.Hexanes was added and a solid precipitated. The precipitate was filteredto provide3-{4-chloro-2-[[2-(4-chloro-phenyl)-2-oxo-ethyl]-(toluene-4-sulfonyl)-amino]-phenyl}-acrylicacid ethyl ester (3.19 g, 76%). mp=162-165° C. ¹H NMR (300 MHz, CDCl₃) d1.38 (t, 3, J=7.2), 2.47 (s, 3), 4.28 (q, 2, J=7.2), 5.00 (bs, 2), 6.23(d, 1, J=16.0), 7.29-7.36 (m, 4), 7.47 (d, 2, J=8.7), 7.54 (d, 1,J=8.4), 7.59 (d, 2, J=8.3), 7.74 (d, 1, J=16.0), 7.88 (d, 2, J=8.7). ¹³CNMR (75 MHz, CDCl₃) d 14.33, 21.62, 57.72, 60.66, 112.49, 120.69,128.07, 129.21, 129.58, 129.70, 131.22, 132.80, 133.83, 134.80, 135.84,138.55, 139.28, 140.38, 144.46, 166.02, 191.70. IR 1720, 1698, 1590,1338, 1313, 1179, 1161, 1089 cm⁻¹. Analysis calculated forC₂₆H₂₃Cl₂NO₅S: C, 58.65; H, 4.35; N, 2.63. Found: C, 58.74; H, 4.56; N,2.72.

Example 296 cis- andtrans-[6-Chloro-2-(4-chloro-benzoyl)-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-aceticAcid Ethyl Ester

To3-{4-chloro-2-[[2-(4-chloro-phenyl)-2-oxo-ethyl]-(toluene-4-sulfonyl)-amino]-phenyl}-acrylicacid ethyl ester (1.00 g, 1.88 mmol) in N,N-dimethylacetamide (5.0 ml)was added potassium carbonate (0.520 g, 3.76 mmol). The reaction mixturewas stirred for four hours, poured in 1N hydrochloric acid (30 ml) andextracted with methyl 1-butyl ether (2×30 ml). The organic extracts weredried with magnesium sulfate, filtered, and concentrated. The resultingsolid was purified by chromatography on silica gel (ethylacetate/hexanes 20/80) to provide[6-chloro-2-(4-chloroenzoyl)-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-aceticacid ethyl ester as a 1 to 9 mixture of cis and trans isomers (0.488 g,49%). Some of the ¹H NMR (300 MHz, CDCl₃) significant signals are: d1.09 (t, J=7.2), 1.19 (t, J=7.2), 2.44 (s), 5.40 (d, J=4.0), 5.99 (d,J=9.7), 6.92 (dd, J=8.1, 1.1), 7.04 (dd, J=8.1, 1.9), 7.52 (d, J=8.4),7.57 (d, J=1.9), 7.73 (d, J=8.3), 7.99 (d, J=8.6). Lc-MS analysis wasperformed on the mixture of diastereoisomers and indicated to productswith identical mass of 531 (M+H⁺).

Example 297 [6-Chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-acetic AcidEthyl Ester

To a solution of 3-[4-chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylicacid ethyl ester (3.00 g, 7.90 mmol) in N,N-dimethylacetamide (15.0 ml)was added potassium carbonate (2.18 g, 15.8 mmol) and2-bromo-4′-chloroacetophenone (2.03 g, 8.69 mmol). The reaction wasstirred 30 minutes and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.54 ml, 23.7mmol) was added. The reaction mixture was stirred one hour, poured into1N hydrochloric acid (30 ml) and extracted with methyl t-butyl ether(2×30 ml). The organic extracts were dried with magnesium sulfate,filtered, and concentrated to provide a solid which was slurried in amixture of methyl t-butyl ether and hexanes to afford[6-chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-acetic acid ethyl ester(2.42 g, 81%). mp=186-188° C. ¹H NMR (300 MHz, CDCl₃) d 1.27 (t, 2,J=7.1), 3.80 (s, 2), 4.11 (q, 2, J=7.1), 7.15 (ddd, 1, J=8.5, 1.7, 0.5),7.28-7.30 (m, 1), 7.48 (d, J=8.3), 7.54-7.57 (m, 1), 7.77 (d, 2, J=8.3),9.16 (bs, 1). ¹³C NMR (75 MHz, CDCl₃) d 15.42, 32.29, 62.45, 113.27,117.60, 122.99, 123.23, 127.85, 130.12, 131.77, 133.61, 137.86, 138.13,140.10, 172.45, 188.25. IR 3305, 1732, 1618, 1323 cm⁻¹. Analysiscalculated for C₁₉H₁₅Cl₂NO₃: C, 60.65; H, 4.02; N, 3.72. Found: C,60.70; H, 3.97; N, 3.71.

Example 298 [6-Chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-acetic Acid

To a solution of [6-chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-aceticacid ethyl ester (200 mg, 0.532 mmol) in methanol (2 ml) and water (0.8ml) was added sodium hydroxide (137 mg, 3.43 mmol). The reaction mixturewas stirred 24 hours, and was concentrated to a low volume. Water (4 ml)was added, the material was transferred to a separatory fumnel and waswashed with dichloromethane (5 ml). The aqueous layer was acidified topH 1 with 1N hydrochloric acid and was extracted with ethyl acetate (15ml). The organic layer was dried over magnesium sulfate, filtered, andconcentrate to afford[6-chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-acetic acid (150 mg, 81%).The ¹H NMR spectrum was identical with the one obtained for the compoundprepared by the method described in example 2.

The chemical structures of the compounds prepared in the Examples 1 to292 are summarized in the following tables.

TABLE

Ex. # (X)_(n) R¹ Z Q 1 6-Cl H ethoxy phenyl 2 6-Cl H OH phenyl 3 6-Cl HONa phenyl 4 6-Cl H OH 2-methylphenyl 5 6-Cl H OH 3-methylphenyl 6 6-ClH OH 4-methylphenyl 7 6-Cl H OH 3-chlorophenyl 8 6-Cl H methoxy4-chlorophenyl 9 6-Cl H OH 4-chlorophenyl 10 6-Cl H OH 3-fluorophenyl 116-Cl H OH 4-fluorophenyl 12 6-Cl H OH 3-bromophenyl 13 6-Cl H OH4-bromophenyl 14 6-Cl H OH 3-CF₃-phenyl 15 6-Cl H OH 4-CF₃-phenyl 166-Cl H OH 3,4-dichlorophenyl 17 4-Cl H OH phenyl 18 5-Cl H OH3-methylphenyl 19 5-Cl H OH 4-chlorophenyl 20 5-Cl H OH 3-chlorophenyl21 5-F H OH 4-chlorophenyl 22 5-F H OH 3-chlorophenyl 23 5-methoxy H OH3-methylphenyl 24 7-Cl H OH phenyl 25 4,5-di-Cl H OH phenyl 26 4,6-di-ClH OH phenyl 27 5,6-di-Cl H OH phenyl 28 6-Cl methyl OH phenyl (racemic)29 6-Cl methyl OH phenyl (less polar antipode) 30 6-Cl methyl OH phenyl(more polar antipode) 31 6-Cl H OH 4-methyl-2-pyridyl 32 6-Cl H OH5-methyl-2-pyridyl 33 6-Cl H methoxy 4-chloro-2-pyridyl 34 6-Cl H OH4-chloro-2-pyridyl 35 6-Cl H OH 2-pyridyl 36 5-Cl H OH4-methyl-2-pyridyl 37 5-Cl H methoxy 6-methyl-2-pyridyl 38 5-Cl H OH6-methyl-2-piridyl 39 6-Cl H OH 1-methyl-2-imidazolyl 40 5-Cl H methoxy2-thiazolyl 41 5-Cl H OH 2-thiazolyl 42 6-Cl H methoxy phenyl 43 6-Cl Hdimethylamino phenyl 44 6-Cl H methylamino phenyl 45 6-Cl H amino phenyl46 6-Cl H N-methoxy-N- phenyl methylamino 47 6-Cl H piperidino phenyl 486-Cl H 4-methyl-1-piperazinyl phenyl 49 6-Cl H 2-cyanoethylamino phenyl50 6-Cl H 2-HO-ethylamino phenyl 51 6-Cl H morpholino phenyl 52 H H OH4-chlorophenyl 53 6-Cl H OH 2-furyl 54 6-Cl H OH cyclohexyl 55 6-Cl H OH4-methoxyphenyl 56 6-Cl H methoxy 4-methoxyphenyl 57 6-Cl H methoxy4-ethyl-2-pyridyl 58 6-Cl H OH 4-ethyl-2-pyridyl 59 5-Cl H methoxy4-ethyl-2-pyridyl 60 5-Cl H OH 4-ethyl-2-pyridyl 61 6-Cl H methoxy4-isopropyl-2-pyridyl 62 6-Cl H OH 4-isopropyl-2-pyridyl 63 5-Cl Hmethoxy 4-isopropyl-2-pyridyl 64 5-Cl H OH 4-isopropyl-2-pyridyl 65 6-ClH methoxy 4-n-propyl-2-pyridyl 66 6-Cl H OH 4-n-propyl-2-pyridyl 67 5-ClH methoxy 4-n-propyl-2-pyridyl 68 5-Cl H OH 4-n-propyl-2-pyridyl 69 6-ClH methoxy 4-tert-butyl-2-pyridyl 70 6-Cl H OH 4-tert-butyl-2-pyridyl 715-Cl H methoxy 4-tert-butyl-2-pyridyl 72 5-Cl H OH4-tert-butyl-2-pyridyl 73 6-Cl H methoxy 3-methyl-2-pyridyl 74 6-Cl H OH3-methyl-2-pyridyl 75 5-Cl H methoxy 3-methyl-2-pyridyl 76 5-Cl H OH3-methyl-2-pyridyl 77 6-Cl H methoxy 6-methyl-2-pyridyl 78 6-Cl H OH6-methyl-2-pyridyl 79 5-Cl H methoxy 5-methyl-2-pyridyl 80 5-Cl H OH5-methyl-2-pyridyl 81 6-Cl H methoxy 5-CF₃-2-pyridyl 82 6-Cl H OH5-CF₃-2-pyridyl 83 5-Cl H methoxy 5-CF₃-2-pyridyl 84 5-Cl H OH5-CF₃-2-pyridyl 85 5-Cl H methoxy 5-Cl-2-pyridyl 86 5-Cl H OH5-Cl-2-pyridyl 87 6-Cl H methoxy 5-Cl-2-pyridyl 88 6-Cl H OH5-Cl-2-pyridyl 89 5-Cl H methoxy 4-Cl-2-pyridyl 90 5-Cl H OH4-Cl-2-pyridyl 91 6-Cl H methoxy 3-pyridyl 92 6-Cl H OH 3-pyridyl 936-Cl H methoxy 4-pyridyl 94 6-Cl H OH 4-pyridyl 95 6-Cl H methoxy4-hydroxymethyl-2-pyridyl 96 6-Cl H OH 4-hydroxymethyl-2-pyridyl 97 5-ClH methoxy 4-hydroxymethyl-2-pyridyl 98 5-Cl H OH4-hydroxymethyl-2-pyridyl 99 5-Cl H methoxy 3,4-dimethyl-2-pyridyl 1005-Cl H OH 3,4-dimethyl-2-pyridyl 101 5-Cl H methoxy4,5-dimethyl-2-pyridyl 102 5-Cl H OH 4,5-dimethyl-2-pyridyl 103 6-Cl Hmethoxy 4,5-dimethyl-2-pyridyl 104 6-Cl H OH 4,5-dimethyl-2-pyridyl 1056-Cl H methoxy 4-methoxy-2-pyridyl 106 6-Cl H OH 4-methoxy-2-pyridyl 1075-Cl H methoxy 4-methoxy-2-pyridyl 108 5-Cl H OH 4-methoxy-2-pyridyl 1096-Cl H methoxy 3,5-dimethyl-2-pyridyl 110 6-Cl H OH3,5-dimethyl-2-pyridyl 111 5-Cl H methoxy 3-F-4-ethyl-2-pyridyl 112 5-ClH OH 3-F-4-ethyl-2-pyridyl 113 6-Cl H methoxy 3-F-4-ethyl-2-pyridyl 1146-Cl H OH 3-C₂H₅O-4-ethyl-2-pyridyl 115 6-Cl H methoxy3-Cl-4-ethyl-2-pyridyl 116 6-Cl H OH 3-Cl-4-ethyl-2-pyridyl 117 5-Cl Hmethoxy 3-Cl-4-ethyl-2-pyridyl 118 5-Cl H OH 3-Cl-4-ethyl-2-pyridyl 1195-Cl H methoxy 4,6-dimethyl-2-pyridyl 120 5-Cl H OH4,6-dimethyl-2-pyridyl 121 6-Cl H methoxy 4,6-dimethyl-2-pyridyl 1226-Cl H OH 4,6-dimethyl-2-pyridyl 123 5,6-di-Cl H methoxy4-methyl-2-pyridyl 124 5,6-di-Cl H OH 4-methyl-2-pyridyl 125 5-methyl Hmethoxy 4-methyl-2-pyridyl 126 5-methyl H OH 4-methyl-2-pyridyl 127 5-FH methoxy 4-methyl-2-pyridyl 128 5-F H OH 4-methyl-2-pyridyl 1295-methoxy H methoxy 4-methyl-2-pyridyl 130 5-methoxy H OH4-methyl-2-pyridyl 131 6-methoxy H methoxy 4-methyl-2-pyridyl 1326-methoxy H OH 4-methyl-2-pyridyl 133 5-ethyl H methoxy4-methyl-2-pyridyl 134 5-ethyl H OH 4-methyl-2-pyridyl 135 5-ethyl Hmethoxy 4-ethyl-2-pyridyl 136 5-ethyl H OH 4-ethyl-2-pyridyl 137 6-ethylH methoxy 4-methyl-2-pyridyl 138 6-ethyl H OH 4-methyl-2-pyridyl 1395-isopropyl H methoxy 4-ethyl-2-pyridyl 140 5-isopropyl H OH4-methyl-2-pyridyl 141 6-CF₃ H methoxy 4-methyl-2-pyridyl 142 6-CF₃ H OH4-methyl-2-pyridyl 143 5-tert-butyl H methoxy 4-methyl-2-pyridyl 1445-tert-butyl H OH 4-methyl-2-pyridyl 145 5-CF₃O H methoxy4-methyl-2-pyridyl 146 5-CF₃O H OH 4-methyl-2-pyridyl 147 5-CF₃O Hmethoxy 4-ethyl-2-pyridyl 148 5-CF₃O H OH 4-ethyl-2-pyridyl 149 6-methylH methoxy 4-methyl-2-pyridyl 150 6-methyl H OH 4-methyl-2-pyridyl 1515-CF₃ H methoxy 4-methyl-2-pyridyl 152 5-CF₃ H OH 4-methyl-2-pyridyl 1535-CF₃ H methoxy 4-ethyl-2-pyridyl 154 5-CF₃ H OH 4-ethyl-2-pyridyl 155 HH methoxy phenyl 156 H H OH phenyl 157 6-methyl H methoxy 4-chlorophenyl158 6-methyl H OH 4-chlorophenyl 159 5-methyl H OH 4-chlorophenyl 1606-methoxy H methoxy 4-chlorophenyl 161 6-methoxy H OH 4-chlorophenyl 1626-CF₃ H OH 4-chlorophenyl 163 5-ethyl H methoxy 4-chlorophenyl 1645-ethyl H OH 4-chlorophenyl 165 5-methoxy H methoxy 4-chlorophenyl 1665-methoxy H OH 4-chlorophenyl 167 5-isopropyl H methoxy 4-chlorophenyl168 5-isopropyl H OH 4-chlorophenyl 169 5-CF₃ H methoxy 4-chlorophenyl170 5-CF₃ H OH 4-chlorophenyl 171 5-CF₃O H methoxy 4-chlorophenyl 1725-CF₃O H OH 4-chlorophenyl 173 6-Cl H methoxy 2-methoxyphenyl 174 6-Cl HOH 2-methoxyphenyl 175 6-Cl H methoxy 3-methoxyphenyl 176 6-Cl H OH3-methoxyphenyl 177 6-Cl H methoxy 3-benzyloxyphenyl 178 6-Cl H OH3-benzyloxyphenyl 179 6-Cl H methoxy 3-hydroxyphenyl 180 6-Cl H OH3-hydroxyphenyl 181 6-Cl H methoxy 4-benzyloxyphenyl 182 6-Cl H OH4-benzyloxyphenyl 183 6-Cl H methoxy 4-hydroxyphenyl 184 6-Cl H OH4-hydroxyphenyl 185 6-Cl H methoxy 4-isopropoxyphenyl 186 6-Cl H OH4-isopropoxyphenyl 187 6-Cl H methoxy 4-biphenyl 188 6-Cl H OH4-biphenyl 189 6-Cl H methoxy 4-CF₃O-phenyl 190 6-Cl H OH 4-CF₃O-phenyl191 5-Cl H methoxy 4-CF₃O-phenyl 192 5-Cl H OH 4-CF₃O-phenyl 193 5-Cl Hmethoxy 4-methoxyphenyl 194 5-Cl H OH 4-methoxyphenyl 195 6-Cl H methoxy4-nitrophenyl 196 6-Cl H OH 4-nitrophenyl 197 6-Cl H methoxy4-methyl-S(O)₂-phenyl 198 6-Cl H OH 4-methyl-S(O)₂-phenyl 199 6-Cl Hmethoxy 4-methyl-S(O)₂-NH-phenyl 200 6-Cl H OH 4-methyl-S(O)₂-NH-phenyl201 6-Cl H OH 2-chlorophenyl 202 6-Cl H OH 2,4-dichlorophenyl 203 6-Cl Hmethoxy 3-F-4-Cl-phenyl 204 6-Cl H OH 3-F-4-Cl-phenyl 205 6-Cl H methoxy4-cyanophenyl 206 6-Cl H methoxy 4-bromophenyl 207 6-Cl H methoxy4-(2-thienyl)phenyl 208 6-Cl H OH 4-(2-thienyl)phenyl 209 6-Cl H methoxy4-(2-furyl)phenyl 210 6-Cl H OH 4-(2-furyl)phenyl 211 6-Cl H methoxy4-(3-pyridyl)phenyl 212 6-Cl H OH 4-(3-pyridyl)phenyl 213 6-Cl H methoxy4-(2-thiazolyl)phenyl 214 6-Cl H OH 4-(2-thiazolyl)phenyl 215 6-Cl Hmethoxy 3-bromophenyl 216 6-Cl H methoxy 3-(2-furyl)phenyl 217 6-Cl H OH3-(2-furyl)phenyl 218 6-Cl methyl methoxy 4-chlorophenyl 219 6-Cl methylOH 4-chlorophenyl 220 5-Cl H methoxy isoquinolin-3-yl 221 5-Cl H OHisoquinolin-3-yl 222 6-Cl H methoxy isoquinolin-3-yl 223 6-Cl H OHisoquinolin-3-yl 224 5-Cl H methoxy 5-methyl-3-isoxazolyl 225 5-Cl H OH5-methyl-3-isoxazolyl 226 6-Cl H methoxy 5-methyl-3-isoxazolyl 227 6-ClH OH 5-methyl-3-isoxazolyl 228 5-Cl H methoxy4-methyl-5-(1,2,3-thiadiazolyl) 229 5-Cl H OH4-methyl-5-(1,2,3-thiadiazolyl) 230 6-Cl H methoxy4-methyl-5-(1,2,3-thiadiazolyl) 231 6-Cl H OH4-methyl-5-(1,2,3-thiadiazolyl) 232 5-Cl H methoxy 5-methyl-2-thiazolyl233 5-Cl H OH 5-methyl-2-thiazolyl 234 6-Cl H methoxy5-methyl-2-thiazolyl 235 6-Cl H OH 5-methyl-2-thiazolyl 236 6-Cl H OH2-thienyl 237 6-Cl H methoxy 3-(HO)(CH₃)₂C-2-furyl 238 6-Cl H OH3-(HO)(CH₃)₂C-2-furyl 239 6-Cl H methoxy 3-methoxymethyl-2-furyl 2406-Cl H OH 3-methoxymethyl-2-furyl 241 6-Cl H OH 1-methyl-2-imidazolyl242 6-Cl H methoxy 1-methyl-2-imidazolyl 243 5-Cl H methoxy1-methyl-2-imidazolyl 244 5-Cl H OH 1-methyl-2-imidazolyl 245 5-Cl Hmethoxy 2-imidazolyl 246 5-Cl H OH 2-imidazolyl 247 6-Cl H methoxy2-imidazolyl 248 6-Cl H OH 2-imidazolyl 249 5-Cl H methoxy4-methyl-2-thiazolyl 250 5-Cl H OH 4-methyl-2-thiazolyl 251 5-Cl Hmethoxy 1-methyl-2-pyrrolyl 252 5-Cl H OH 1-methyl-2-pyrrolyl 253 5-Cl Hmethoxy 2-methyl-4-thiazolyl 254 5-Cl H OH 2-methyl-4-thiazolyl 255 5-ClH methoxy 5-thiazolyl 256 5-Cl H OH 5-thiazolyl 257 6-Cl H methoxy4-methyl-2-thiazolyl 258 6-Cl H OH 4-methyl-2-thiazolyl 259 5-Cl Hmethoxy 3-carboxyl-5-isoxazolyl 260 5-Cl H OH 3-carboxyl-5-isoxazolyl261 6-Cl H methoxy cyclopropyl 262 6-Cl H OH cyclopropyl 263 6-Cl Hmethoxy cyclobutyl 264 6-Cl H OH cyclobutyl 265 5-tert-butyl H methoxy4-chlorophenyl 266 5-tert-butyl H OH 4-chlorophenyl 267 6-Cl Hdimethylamino 4-methyl-2-pyridyl 268 6-Cl H methylamino4-methyl-2-pyridyl 269 5-Cl H HO—(CH₂)₂—NH— 4-methyl-2-pyridyl 270 5-ClH methoxyamino 4-methyl-2-pyridyl 271 5-Cl H 1-piperazinyl4-methyl-2-pyridyl 272 5-Cl H H₂N—(CH₂)₂—NH— 4-methyl-2-pyridyl 273 5-ClH 3-amino-1-pyrrolidinyl 4-methyl-2-pyridyl 274 5-F,6-Cl H methoxy4-chlorophenyl 275 5-F,6-Cl H OH 4-chlorophenyl 276 5-F,6-Cl H methoxy4-methyl-2-pyridyl 277 5-F,6-Cl H OH 4-methyl-2-pyridyl 278 6-Cl Hmethoxy 4-(HO)(H₃C)CH-2-pyridyl 279 6-Cl H OH 4-(HO)(H₃C)CH-2-pyridyl280 6-Cl H OH 4-ethyl-3-F-2-pyridyl 281 6-Cl H OH 2-nitrophenyl 282 6-ClH OH 2,4-dimethoxyphenyl 283 6-Cl H OH 4-CHF₂O-phenyl 284 6-Cl H OH2,5-dimethoxyphenyl 285 5-acetyl H methoxy 4-Cl-phenyl 286 5-acetyl H OH4-Cl-phenyl 287 6-F H methoxy 4-methyl-2-pyridyl 288 6-F H OH4-methyl-2-pyridyl 289 6-F H methoxy 4-Cl-phenyl 290 6-F H OH4-Cl-phenyl 291 5-CH₃S— H methoxy 4-methyl-2-pyridyl 292 5-CH₃S— H OH4-methyl-2-pyridyl

What is claimed is:
 1. A compound of the following formula:

or the pharmaceutically acceptable salts thereof wherein Z is OH, C₁₋₆alkoxy, —NR²R³ or a group of the formula (II) or (III):

wherein r is 1, 2, 3 or 4, Y is a direct bond, O, S or NR⁴, and W is OHor —NR²R³; Q is selected from the following: (a) phenyl optionallysubstituted with one, two or three substituents independently selectedfrom (a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH,—C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl, (a-2)aryl or —O—(CH₂)_(n)-aryl, and the aryl or aryl moiety being optionallysubstituted with one, two or three substituents independently selectedfrom halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN, (a-3) 5-membered monocyclicaromatic group optionally substituted with one, two or threesubstituents independently selected from halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylaminoand CN, (a-4) 6-membered monocyclic aromatic group optionallysubstituted with one, two or three substituents independently selectedfrom halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN, (b) a 6-membered monocyclicaromatic group containing one, two, three or four nitrogen atom(s), andsaid monocyclic aromatic group being optionally substituted with one,two or three substituents independently selected from the above group(a-1), (a-2), (a-3) and (a-4), (c) a 5-membered monocyclic aromaticgroup containing one heteroatom selected from O, S and N and optionallycontaining one, two or three nitrogen atom(s) in addition to saidheteroatom, and said monocyclic aromatic group being optionallysubstituted with one, two or three substituents independently selectedfrom the above group (a-1), (a-2), (a-3) and (a-4); (d) C₃₋₇ cycloalkyloptionally substituted with one or two substituents independentlyselected from OH, C₁₋₄ alkyl, halo and halo-substituted C₁₋₄ alkyl; and(e) a benzo-fuzed heterocycle optionally substituted with one, two orthree substituents independently selected from the group (a-1); R¹ ishydrogen, C₁₋₄ alkyl or halo; R² and R³ are independently H, OH, C₁₋₄alkoxy, C₁₋₄ alkyl or C₁₋₄ alkyl substituted with halo, OH, C₁₋₄ alkoxy,NH₂ or CN; R⁴ is hydrogen or C₁₋₄ alkyl; X is independently selectedfrom halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²NR³, acetyl,—COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl;and n is 0, 1, 2, 3 or
 4. 2. A compound according to claim 1, wherein Zis OH, C₁₋₆ alkoxy, dimethylamino, methylamino, amino,N-methoxy-N-methylamino, 2-cyanoethylamino, 2-hydroxyethylamino,pyrrolidinyl, piperidino, piperazinyl, N-methyl-piperazinyl, morpholino,methoxyamino, piperazinyl, aminoPyrrolidinyl or aminoethylamino.
 3. Acompound according to claim 2, wherein Z is OH or C₁₋₆ alkoxy; and Q isselected from the following: (a) phenyl optionally substituted with one,two or three substituents independently selected from (a-1) halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH, —C(O)O—C₁₋₄alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl, (a-2) aryl or—O—(CH₂)_(n)-aryl, and the aryl or aryl moiety being optionallysubstituted with one, two or three substituents independently selectedfrom halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH_(2, di-(C) ₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN, (a-3) 5-membered monocyclicaromatic group optionally substituted with one, two or threesubstituents independently selected from halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylaminoand CN, (a-4) 6-membered monocyclic aromatic group optionallysubstituted with one, two or three substituents independently selectedfrom halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN, (b) a 6-membered monocyclicaromatic group containing one, two, three or four nitrogen atom(s), andsaid monocyclic aromatic group being optionally substituted with one,two or three substituents independently selected from the above group(a-1), (a-2), (a-3) and (a-4), (c) a 5-membered monocyclic aromaticgroup containing one heteroatom selected from O, S and N and optionallycontaining one, two or three nitrogen atom(s) in addition to saidheteroatom, and said monocyclic aromatic group being optionallysubstituted with one, two or three substituents independently selectedfrom the above group (a-1), (a-2), (a-3) and (a-4); (d) C₃₋₇ cycloalkylselected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, andthe said cycloalkyl being optionally substituted with one substituentselected from OH, methyl, ethyl, propyl, F, Cl and CF₃; and (e) abenzo-fuzed heterocycle selected from quinolyl, isoquinolyl, cinnolinyl,quinoxalinyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl,benzofuranyl; benzothiophenyl and indolyl, and the benzo-fuzedheterocycle being optionally substituted with one, two, or threesubstituents independently selected from the group (a-1).
 4. A compoundaccording to claim 3, wherein Q is selected from the following: (a)phenyl optionally substituted with one, two or three substituentsindependently selected from (a-1) halo, C₁₋₄ alkyl, halo-substitutedC₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN,HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl,aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH, —C(O)O—C₁₋₄ alkyl, C₁₋₄alkylsulfonylamino and C₃₋₇ cycloalkyl, (a-2) aryl or —O—(CH₂)_(n)-aryl,and the aryl or aryl moiety being optionally substituted with one, twoor three substituents independently selected from halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylaminoand CN, (a-3) 5-membered monocyclic aromatic group optionallysubstituted with one, two or three substituents independently selectedfrom halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN, (a-4) 6-membered monocyclicaromatic group optionally substituted with one, two or threesubstituents independently selected from halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylaminoand CN, (b) a 6-membered monocyclic aromatic group containing one, two,three or four nitrogen atom(s), and said monocyclic aromatic group beingoptionally substituted with one, two or three substituents independentlyselected from the above group (a-1), (a-2), (a-3) and (a-4); (c) a5-membered monocyclic aromatic group containing one heteroatom selectedfrom O, S and N and optionally containing one, two or three nitrogenatom(s) in addition to said heteroatom, and said monocyclic aromaticgroup being optionally substituted with one, two or three substituentsindependently selected from the above group (a-1), (a-2), (a-3) and(a-4); (d) cyclopropyl, cyclobutyl and cyclohexyl; and (e) quinolyl orisoquinolyl, and said quinolyl or isoquinolyl being optionallysubstituted with one substituent selected from the group halo, C₁₋₄alkyl, NH₂, OH, C₁₋₄ alkoxy and C₁₋₄ halo-substituted alkyl.
 5. Acompound according to claim 4, wherein Z is OH, C₁₋₆ alkoxy; Q isselected from the following: (a) phenyl optionally substituted with one,two or three substituents independently selected from (a-1) halo, C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄alkylamino, CN, HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄alkylsulfonyl, aminosulfonyl, —NH₂S(O)₂NR²R³, acetyl, —COOH, —C(O)O—C₁₋₄alkyl, C₁₋₄ alkylsulfonylamino and C₃₋₇ cycloalkyl, (a-2) aryl or—O—(CH₂)_(n)-aryl, and the aryl or aryl moiety being optionallysubstituted with one, two or three substituents independently selectedfrom halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN, (a-3) 5-membered monocyclicaromatic group optionally substituted with one, two or threesubstituents independently selected from halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylaminoand CN, (a-4) 6-membered monocyclic aromatic group optionallysubstituted with one, two or three substituents independently selectedfrom halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino and CN, (b) a 6-membered monocyclicaromatic group containing one, two, three or four nitrogen atom(s), andsaid monocyclic aromatic group being optionally substituted with one,two or three substituents independently selected from the above group(a-1), (a-2), (a-3) and (a-4), (c) a 5-membered monocyclic aromaticgroup containing one heteroatom selected from O, S and N and optionallycontaining one, two or three nitrogen atom(s) in addition to saidheteroatom, and said monocyclic aromatic group being optionallysubstituted with one, two or three substituents independently selectedfrom the above group (a-1), (a-2), (a-3) and (a-4); and (e) isoquinolyl;R¹ is hydrogen or C₁₋₄ alkyl; R² and R³ are independently H or methyl; Xis independently selected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄alkyl, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,NO₂, NH₂, di-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino, CN, HO—(C₁₋₄)alkyl,C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, aminosulfonyl,—NH₂S(O)₂NR²NR³, acetyl, —COOR⁴, C₁₋₄ alkylsulfonylamino and C₃₋₇cycloalkyl; and n is 0, 1, 2, or
 3. 6. A compound according to claim 5,wherein Z is OH, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,iso-butoxy or tert-butoxy; Q is selected from the following: (a) phenyloptionally substituted with one or two substituents independentlyselected from (a-1) halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH,C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio,HO—(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, —COOH, C₁₋₄ alkylsulfonylamino,nitro, C₁₋₄ alkylsulfonyl and cyano, (a-2) phenyl or benzyloxy, and thephenyl or phenyl moiety of benzyloxy being optionally substituted withone substituent selected from C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl,halo, OH, C₁₋₄ alkoxy, halo-substituted C₁₋₄ alkoxy and NH₂, (a-3)5-membered monocyclic aromatic group selected from imidazolyl,thiazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, triazolyl, oxazolyl,isoxazolyl, thiadiazolyl and pyrazolyl, and the 5-membered monocyclicaromatic group optionally being substitued with one substituent selectedfrom C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, halo, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy and NH₂, (a-4) 6-membered monocyclicaromatic group selected from pyridyl, pyrazinyl, pyrimidinyl andpyridazinyl, and the 6-membered monocyclic aromatic group optionallybeing substitued with one substituent selected from C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, halo, OH, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkoxy and NH₂, (b) a 6-membered monocyclic aromatic group selectedfrom pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, and saidmonocyclic aromatic group being optionally substituted with one or twosubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4), (c) a 5-membered monocyclic aromatic group selectedfrom imidazolyl, thiazolyl, fiiryl, thienyl, pyrrolyl, tetrazolyl,triazolyl, oxazolyl, isoxazolyl, thiadiazolyl and pyrazolyl, and saidmonocyclic aromatic group being optionally substituted with one or twosubstituents independently selected from the above group (a-1), (a-2),(a-3) and (a-4); R¹ is hydrogen, methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl or tert-butyl; X is independently selected from halo,C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, OH, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkylthio, NO₂, NH₂, di-(C₁₋₄alkyl)amino, C₁₋₄ alkylamino, CN, HO-(C₁₋₄)alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkylsulfonyl and aminosulfonyl; and n is 0, 1, 2, or
 3. 7.A compound according to claim 6, wherein Z is OH, methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, iso-butoxy or tert-butoxy; Q isselected from the following: (a) phenyl optionally substituted with oneor two substituents independently selected from (a-1) fluoro, chloro,bromo, iodo, methyl, ethyl, propyl, butyl, CH₂F, CHF₂, CF₃, methoxy,ethoxy, n-propoxy, n-butoxy, isopropoxy, CH₂F—O—, CHF₂—O—, CF₃—O—,methylthio, ethylthio, hydroxymethyl, methoxymethyl, methoxyethyl,ethoxymethyl, hydroxy, nitro, methylsulfonyl, cyano, (HO)(H₃C)₂C—,acetyl and methylsulfonylamino, (a-2) phenyl or benzyloxy, and thephenyl or phenyl moiety of benzyloxy being optionally substituted withone substituent selected from methyl, ethyl, propyl, CF₃, F, Cl, OH,methoxy, ethoxy and NH₂, (a-3) 5-membered inonocyclic aromatic groupselected from furyl, thienyl and pyrrolyl, and the 5-membered monocyclicaromatic group optionally being substituted with one substituentselected from methyl, ethyl, propyl, CF₃, F, Cl, OH, methoxy, ethoxy andNH₂, (a-4) pyridyl optionally substituted with one substituent selectedfrom methyl, ethyl, propyl, CF₃, F, Cl, OH, methoxy, ethoxy and NH₂, (b)pyridyl optionally substituted with one, two or three substituentsindependently selected from the above group (a-1), (a-1), (a-2), (a-3)and (a-4), (c) imidazolyl, thiazolyl, furyl, thienyl, isoxazolyl,1,2,3-thiadiazolyl or pyrrolyl, and said imidazolyl, thiazolyl, furyl,thienyl, isoxazolyl, 1,2,3-thiadiazolyl or pyrrolyl being optionallysubstituted with one or two substituents independently selected from theabove group (a-1), (a-2), (a-3) and (a-4); R¹ is hydrogen, methyl,ethyl, n-propyl, iso-propyl; X is independently selected from fluoro,chloro, bromo, methyl, ethyl, propyl, butyl, CH₂F, CHF₂, CF₃, methoxy,CFO or ethoxy; and n is 0, 1 or
 2. 8. A compound according to claim 7,wherein Z is OH, ethoxy or methoxy; Q is phenyl, chlorophenyl,fluorophenyl, bromophenyl, methylphenyl, methoxyphenyl, (furyl)phenyl,trifluoromethylphenyl, trifluoromethoxyphenyl, pyridyl, methylpyridyl,ethylpyridyl, propylpyridyl, dimethylpyridyl, chloropyridyl,fluoropyridyl, trifluoromethylpyridyl, methoxypyridyl,(ethyl)(ethoxy)pyridyl, (chloro)(ethyl)pyridyl, thiazolyl,methylthiazolyl, furyl, methoxymethylfuryl, isoquinolyl, cyclohexyl,methoxyphenyl, (fluoro)(ethyl)pyridyl, dimethylpyridyl or(ethoxy)(ethyl)pyridyl; R¹ is hydrogen; X is fluoro, chloro, methyl,ethyl, isopropyl, tert-butyl, CF₃ or methoxy; and n is 1 or
 2. 9. Acompound according to claim 8, wherein Z is OH, ethoxy or methoxy; Q isphenyl, chlorophenyl, pyridyl, methylpyridyl, ethylpyridyl,propylpyridyl or chloropyridyl; R¹ is hydrogen; X is fluoro, chloro,methyl or CF₃; and n is 1 or
 2. 10. A compound according to claim 1,selected from ethyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid, sodium salt;[6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(3,4-dichloro benzoyl)-1H-indol-3-yl]acetic acid;(2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid;[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;[5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;(2-benzoyl-7-chloro-1H-indol-3-yl)acetic acid;(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; less polarantipode, 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; more polarantipode, 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;(2-benzoyl-6-chloro-1H-indol-3-yl)-N,N-dimethylacetamide;(2-benzoyl-6-chloro-1H-indol-3-yl)-N-methylacetamide;(2-benzoyl-6-chloro-1H-indol-3-yl)acetamide;(2-benzoyl-6-chloro-1H-indol-3-yl)-N-methoxy-N-methylacetamide;2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-piperidino-1-ethanone;2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-(4-methyl-1-piperazinyl)-1-ethanone;(2-benzoyl-6-chloro-1H-indol-3-yl)-N-(2-cyanoethyl)acetamide;(2-benzoyl-6-chloro-1H-indol-3-yl)-N-(2-hydroxyethyl)acetamide;2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-morpholino-1-ethanone;[2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetate;[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid;methyl[2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetate;[2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(3-methylpynidine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate,[5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;methyl[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;methyl[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;methyl[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;methyl[5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;methyl[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;methyl[6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;methyl[5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;methyl[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate;[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]aceticacid;methyl[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate;[2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]aceticacid;methyl[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate;[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]aceticacid;methyl[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid;methyl[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid; methyl(2-benzoyl-1H-indol-3-yl)acetate;(2-benzoyl-1H-indol-3-yl)acetic acid;methyl[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate;[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid;[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid;methyl[6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;[6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[2-(4-chlorobenzoyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid;methyl[2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetate;[2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetic acid;methyl[2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetate;[2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetic acid;methyl[2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetate;[2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetic acid;methyl[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;methyl[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate;[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(3-yoxybylenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-benzoxybenzyloyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;methyl(6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetate;[6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetic acid;methyl(6-chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetate;[6-chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetic acid;[6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-cyanobenzoyl)-1H-indol-3-yl]acetate;methyl[6-chloro-2-[4-bromobenzoyl]-1H-indol-3-yl]acetate;methyl[6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetate;[6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate;[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetate;[6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetate;[6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(3-bromobenzoyl)-1H-indol-3-yl]acetate;methyl[6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetate;[6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid; methyldl-2-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]propionate;dl-2-[2-(4-chlorobenzoyl)-6-chloro-1H-indol-3-yl]propionic acid;methyl[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]aceticacid;methyl[6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]aceticacid;methyl[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(2-thienyl)carbonylindol-3-yl]acetic acid;methyl[6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetate;[6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]aceticacid;methyl[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate;[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetate;methyl[5-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro -2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro -2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-[3-(ethoxycarbonyl)isoxazole-5-carbonyl]-1H-indol-3-yl]acetate;[5-chloro-2-[3-(carboxy)isoxazole-5-carbonyl]-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetate;[6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetate;[6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetic acid;methyl[5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;[5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N,N-dimethylacetamide;[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-methylacetamide;[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-hydroxyethyl)acetamide;[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-methoxyacetamide;2-[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-piperazinyl-1-ethanone;[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-aminoethyl)acetamide;2-[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-(3-amino-1-pyrrolidinyl)-1-ethanone;[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;methyl[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;methyl[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid; [6-chloro-2-(2-nitrobenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(2,4-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-difuluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(2,5-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;[5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate;methyl[6-fluoro-2-(4-methylpyridine-2-carbonyl]-1H-indol-3-yl]acetate;[6-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;[6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[2-(4-methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic acid;[2-(4-methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic acid,and a salt thereof.
 11. A compound according to claim 1 selected from(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid; methyl[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetaticacid;methyl[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;methyl[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;methyl[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid;methyl[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;methyl[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate;[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;methyl[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate,and a salt thereof.
 12. A compound according to claim 10, selected from(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]aceticacid; [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;[5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid; [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid; [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]aceticacid;[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid; [6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]aceticacid; [6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]aceticacid; [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid, and asalt thereof.
 13. A pharmaceutical composition useful for the treatmentof a medical condition in which prostaglandins are, implicated aspathogens, which comprises a compound of the formula (I) of claim 1, anda pharmaceutically inert carrier.
 14. A method for the treatment of amedical condition in which prostaglandins are implicated as pathogens,in a mammalian subject, which comprises administering to said subject apharmaceutical composition according to claim 13, wherein said medicalcondition is selected from the group consisting of pain, fever andinflammation associated with rheumatic fever, symptoms associated withinfluenza or other viral infections, common cold, low back and neckpain, dysmenorrhea, headache, toothache, sprains and strains, myositis,neuralgia, synovitis, arthritis including rheumatoid arthritis,degenerative joint disease including osteoarthritis, gout, ankylosingspondylitis, systemic lupus erythematosus, juvenile arthritis, bursitis,burns, and injury following surgical and dental procedures.